Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:14]Br.Cl>CO.O>[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:14]=[O:5]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1c(Cl)ccc(Cl)c1CBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Cl)ccc(Cl)c1C=O
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
122.4 g (0.68 mol) of a 30% strength solution of sodium methoxide are dissolved in 1030 ml of methanol, and 56.4 g ( 0.57 mol) of 90% pure 2-nitropropane and 188.5 g (0.52 mol) of 61.6% pure 3,6-dichloro-2-methylbenzyl bromide are then added. The reaction is exothermic to 53° C., and the mixture is then stirred for 90 min. The reaction mixture is poured into 2.5 l of water, the pH is adjusted to pH 7.0 using 10% strength HCl, the mixture is extracted three times with 1 l of ethyl acetate, and the organic phases are combined, washed twice with 500 ml of saturated NaCl solution, dried over Na2SO4 and concentrated under reduced pressure: the 161.0 g of crude product are distilled using a 10 cm column packed with 10 mm Raschig rings. The crystals from the last fractions are filtered. This gives 9.8 g comprising 85.9% of the desired product and 4.5% and 6.9% of isomers. Yield: 9.7%. The residue is distilled over a Spaltrohr column, giving another 3.2 g of 94.3% pure product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[F:27][C:28]1([F:32])[CH2:31][N:30]([C:19]([C:18]([NH:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:14][CH2:13]3)[N:8]=2)=[O:16])([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:21])[CH2:29]1
Reactant: FC1(F)CNC1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e=422.0 [M+H]+.
Reaction SMILES: [P:1]([O-:28])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].COC(C)(C)C.N12CCCNC1C=CCCC2.[C:46]([S:50][CH2:51][C:52](=[O:54])[CH3:53])([CH3:49])([CH3:48])[CH3:47]>C1(C)C=CC=CC=1.CS(C)=O>[C:46]([S:50][CH2:51][C:52]([OH:54])([CH3:53])[P:1]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:28])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCCCCCCCCCCOP([O-])OCCCCCCCCCCCC
Reactant: CC(=O)CSC(C)(C)C
Agent: C1=CC2NCCCN2CCC1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCC)C(C)(O)CSC(C)(C)C
Temperature: 60 °C

Procedure:
23.0 g (55 mmol) of didodecyl phosphite are initially introduced into a mixture of 20 ml of tert-butyl methyl ether and 5 ml of dimethyl sulfoxide. 1.0 g of 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU) are added, and 8.04 g (55 mmol) of (t-butylthio)acetone are then added dropwise at 30° C. The reaction mixture is heated for 5 hours at 60° C., cooled, diluted with 150 ml of toluene and washed with 100 ml of water. The organic phase is dried over sodium sulfate, and the solvent and remainders of the educts are distilled off in vacuo (finally at 0.5 mbar and 55° C. bath temperature).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([NH:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])=O.P([O-])([O-])(O)=O.[K+].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[N:8]=2)[N:7]=1
Reactant: O=C(CBr)NC(=O)C1CC1
Reactant: Nc1ccc(Cl)nn1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(Cl)ccc2n1)C1CC1

Procedure:
6-Chloropyridazin-3-amine, N-(2-bromoacetyl)cyclopropanecarboxamide, and potassium hydrogenphosphate were mixed in DMA at 75° C. to provide N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide. N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide was reacted with [1,2,4]triazolo[4,3-a]pyridine-3-thiol and K2CO3 in DMA at 145° C. and 100 psi N2 to provide N-(6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclo-propanecarboxamide.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:10]2[C:9](=[O:24])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31](F)([F:33])[F:32])[CH:26]=2)[C:3]1=[O:35].FC(F)C1C=C(N2C3CCCC(=O)C=3C(C3C=CC(C#N)=CC=3S(C)(=O)=O)NC2=O)C=CC=1>>[F:33][CH:31]([F:32])[C:27]1[CH:26]=[C:25]([N:4]2[C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:24])[C:10]=3[CH:11]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[S:20]([CH3:23])(=[O:22])=[O:21])[N:2]([CH3:1])[C:3]2=[O:35])[CH:30]=[CH:29][CH:28]=1
Reactant: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CCC2
Product: CN1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The title compound is prepared in analogy to (S)-4-(3-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 48), using 4-(1-(3-(difluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 19, 60 mg, 0.13 mmol) as starting material. Yield: 20 mg, ESI mass spectrum [M+H]+=486; Retention time HPLC: 0.99 min (Z017_S04).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2=[N:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:15]2[N:14]=1.O>CN(C)C=O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[N:15]3[N:14]=[C:13]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[C:22]4[C:17]([C:16]3=[N:23][N:24]=2)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4ccc(C#N)cc4)nn23)cc1
Yield: 84.7 %

Procedure:
295 mg of 4-amino-benzonitrile and 6 mg of sodium hydride (60%) in 2.5 ml of N,N-dimethylformamide are treated with 100 mg of 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) at ambient temperature. After 10 min the reaction mixture is added to water, the precipitate is filtered with suction and the solid is recrystallized from N,N-dimethylformamide to yield 107 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:22][CH2:23][N:24]1[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3ccccc3F)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 50 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(2-fluorophenyl)acetic acid and (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine as starting materials. Product was obtained as an off-white solid (50%). LC/MS (Method B) 4.53 min, [M+1]+ 503.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5].[CH2:13](Br)[C:14]#[CH:15]>>[CH3:1][N:2]([CH2:15][C:14]#[CH:13])[C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5]
Reactant: CN[C@H](CO)Cc1ccccc1
Reactant: C#CCBr
Product: C#CCN(C)[C@H](CO)Cc1ccccc1

Procedure:
Compound 1c is synthesized according to general procedure H from starting material 1b using 2.5 mmol of propargyl bromide (298 mg). The desired compound is obtained in 60% yield (243 mg, 1.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]([NH2:5])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Cl)c1C#N
Product: Cc1cccc(Cl)c1C(N)=O

Procedure:
A solution of 2-chloro-6-methylbenzonitrile (2.0 g) in conc. sulphuric acid (10 mL) was heated at 100° C. for 3-4 h. The reaction mass was quenched in ice-water and the solid obtained was filtered. The precipitate was suck dried to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.28 (s, 3H), 7.21-7.27 (m, 3H), 7.65 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[Cs+]>C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:17]([C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[CH:16][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 79.2 %

Procedure:
To N-methylpyrrolidone (25 ml) were added 4-chloro-3-nitrobenzonitrile (1.79 g, 9.80 mmol), phenylboronic acid (1.53 g, 12.5 mmol), cesium fluoride (3.90 g, 25.7 mmol) and bis(triphenylphosphine)palladium(II) dichloride (447 mg, 0.637 mmol), and the mixture was stirred with heating at 100° C. for 9 hr. The reaction mixture was cooled, diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The organic layer was extracted and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.74 g, yield 79%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.O.[ClH:35]>CO.C(O)C>[ClH:35].[ClH:35].[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide (8.5 g, 21 mmol), hydrazine monohydrate (1.5 g, 30 mmol) in methanol (60 ml) was heated at reflux for 2 hours. At the end of the reaction, methanol was removed to leave a crude solid. To this was added water (60 ml), then the mixture was acidified with HCl to pH 1. The insolubles were filtered with the aid of a pad of Celite. The aqueous solution was basified with 50% NaOH, (pH 13), then extracted with dichloromethane. The combined dichloromethane solution was washed with brine, then dried to a colorless oil (4.5 g). The analytical sample (1.5 g) was prepared by treating the oil with HCl in ethanol at 0° C. The 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride was obtained as white crystals, 2.03 g, m.p.=231°-234° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([C:12]2(O)[C@H:17]([O:18][Si](C)(C)C)[C@@H:16]([O:23][Si](C)(C)C)[C@H:15]([O:28][Si](C)(C)C)[C@@H:14]([CH2:33][O:34][Si](C)(C)C)[O:13]2)=[CH:4][C:3]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1.CS(O)(=O)=O.C([O-])(O)=O.[Na+].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1COCC1.C(Cl)Cl.CC#N.O>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([C@H:12]2[C@H:17]([OH:18])[C@@H:16]([OH:23])[C@H:15]([OH:28])[C@@H:14]([CH2:33][OH:34])[O:13]2)=[CH:4][C:3]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc(C3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)c3c(c2Cl)CC(C)O3)cc1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CC(C)O3)cc1
Temperature: -30 °C

Procedure:
To a solution of the crude alcohol (4.46 g, 5.79 mmol) in THF (50 mL) were added CH3SO3H (0.6 N in MeOH, 18 mL, 10.4 mmol) at −78° C. The mixture was allowed to slowly warm to −30° C. To a mixture was added aq. saturated NaHCO3 solution (50 mL) to quench the reaction. After dilution with water, the mixture was stirred at room temperature for 30 min and extracted with EtOAc (100 mL×2). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude (3R,4S,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (2.52 g) was carried on to the next step without further purification. To a solution of the triol compound (2.52 g) in CH2Cl2/CH3CN (25 mL/25 mL) were added triethylsilane (1.7 mL, 10.2 mmol) and boron trifluoride diethyl etherate (1.3 mL, 10.2 mmol) at −60° C. The mixture was allowed to slowly warm to −10° C. To a mixture was added aq. saturated NaHCO3 solution (20 mL) to quench the reaction. The reaction mixture was stirred at r.t. and evaporated in vacuo to remove CH2Cl2 and CH3CN. The mixture was extracted with EtOAc (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified using reverse phase preparative HPLC to provide the title compound E011 (81 mg, 2.8% (3-steps)).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: COCCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methoxy-propyl)-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51N4O3Cl2 [(M+H)+] 693.3333, observed 693.3334.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][C:6]1(O)[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Temperature: 70 °C

Procedure:
5-(3-Dimethylaminopropyl)-5-hydroxy-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (13.62 g., 0.037 mole) is dissolved in 136 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 68 ml., is added and the solution heated under reflux for 1 hour in a water-bath at 70° C. The dark green solution is cooled and poured into 250 ml. of ice-water. The mixture is rendered alkaline with 10 N. sodium hydroxide solution while stirring and cooling and extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and the benzene distilled under reduced pressure. The mixed geometric isomers of 5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene is obtained as a brown oily residue in a yield of 13.19 g. (theory, 13.08 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.Cl.N[C@@H]1CC[CH2:16][CH2:15][C@H:14]1[OH:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(O)(C)C.[Ni](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:15]2[CH2:14][O:19][CH2:16]2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccc(C2COC2)cn1
Temperature: 80 °C
Yield: 388.3 %

Procedure:
To a solution of 2-chloropyridine-5-boronic acid (315 mg, CAS 444120-91-6) in isopropanol (2 ml) in a 10 mL microwave vial were added nickel iodide (18.8 mg), trans-2-aminocyclohexanol hydrochloride (9.21 mg) and sodium bis(trimethylsilyl)amide (387 mg). Argon was bubbled into the reaction mixture for 5 min. A solution of 3-iodo-oxetane (190 mg, CAS 26272-85-5) in isopropanol (0.25 ml) was then added. The vial was then capped and heated in the microwave at 80° C. for 20 min. TLC at t=20 min showed the reaction was complete. The reaction mixture was diluted with EtOH and filtered through celite. The filter cake was washed with EtOH and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford 2-chloro-5-oxetan-3-yl-pyridine (40 mg, 24%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1>C1COCC1.[NH4+]>[Br:8][C:9]1[C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: COc1cc(Cl)c(Br)cn1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OCC2CC2)c(Br)cn1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of cyclopropylmethanol (446 mg, 6.18 mmol) in THF (10 mL) was added NaH (247 mg, 6.18 mmol, 60% in mineral oil) in one portion at 0° C. The reaction mixture was warmed up to 20° C. over a period of 30 mins and stirred at 20° C. for 10 mins. Then 5-bromo-4-chloro-2-methoxypyridine (550 mg, 2.47 mmol) was added in one portion and the mixture was stirred at 70° C. for 4 hours. The mixture was diluted with saturated ammonium aqueous solution (50 mL) and extracted by EtOAc (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (PE: EA=20:1 to 10:1) to afford the title compound (450 mg, 70.6%) as colorless oil. 1H NMR: (CDCl3, 400 MHz) δ: 8.11 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.89-3.88 (m, 2H), 1.39-1.27 (m, 1H), 0.70-0.67 (m, 2H), 0.46-0.43 (m, 2H). LCMS (M+H)+=258.0 (M+1)+; 260.0
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[CH2:15]([NH:22][C:8]1[C:9]([Cl:13])=[CH:10][C:11]([F:12])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1nc(F)c(Cl)cc1F
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(Cl)cc1F
Temperature: 150 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To 10 ml of N-methylpyrrolidone was added 6.8 g of 2-(t-butylamino)-5-chloro-3,6-difluoropyridine together with 8.0 g of benzylamine, and the mixture was stirred at 150° C. for one day, and allowed to cool. After 80 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 100 g; eluent: chloroform:n-hexane, 1:1) to obtain about 7.0 g of the title compound as a pale brown crude oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1c[nH]c(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
5-Methyl-2(1H)-pyridinone (50 g, 0.46 mol) was suspended in dichloromethane (500 mL). N-bromosuccinimide (82 g, 0.46 mol) was added in portions with cooling. Addition was finished after 15 min; the mixture was stirred for 1 h at room temperature and afterwards partitioned between dichloromethane and water. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by crystallization from ethyl acetate to yield 55 g of the title compound as a light yellow solid, mp 156-161° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[OH:18][CH:16]1[CH2:17][N:14]([C:2]2[N:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=2)[CH2:15]1
Reactant: COC(=O)Cc1cccc(Br)n1
Reactant: OC1CNC1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: COC(=O)Cc1cccc(N2CC(O)C2)n1
Temperature: 25 °C

Procedure:
The solution of methyl 2-(6-bromopyridin-2-yl)acetate (500.0 mg, 2.17 mmol), azetidin-3-ol hydrochloride (285.9 mg, 2.61 mmol), CuI (248.3 mg, 1.30 mmol), L-proline (149.7 mg, 1.30 mmol) and Cs2CO3 (24.7 g, 75.7 mmol) in DMSO (6 mL) was stirred at 90 degree for 12 h under N2. After cooling to room temperature, the reaction mixture was filtered, diluted with H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:23](=[O:24])[NH:22][CH:21]=[CH:20][C:14]=4[N:15]=[C:16](SC)[N:17]=3)=[CH:10][C:4]=2[CH2:3]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:16]1[N:17]=[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[CH2:6][S:2](=[O:1])(=[O:25])[CH2:3][C:4]=3[CH:10]=2)[C:13]2[C:23](=[O:24])[NH:22][CH:21]=[CH:20][C:14]=2[N:15]=1
Reactant: CSc1nc(Nc2ccc3c(c2)CS(=O)(=O)C3)c2c(=O)[nH]ccc2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nc(Nc2ccc3c(c2)CS(=O)(=O)C3)c2c(=O)[nH]ccc2n1

Procedure:
The compound was prepared from 4-[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one using mCPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar to that described for Example 1 (Scheme 2).