Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH2:12](O)C>[Pd]>[ClH:1].[CH3:12][CH:11]1[C:6]2([O:5][CH2:4][CH2:3][O:2]2)[CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CCO
Reactant: C1CNCC2(C1)OCCO2
Agent: [Pd]
Agent: Cl
Product: CC1CCNCC12OCCO2
Reaction time: 24 h
Yield: 99 %

Procedure:
A slurry of palladium on carbon (10%, 90 mg) in ethanol (10 mL) was added to a solution of (RS)-10-methyl-7-phenylmethyl)-1,4-dioxa-7-azaspiro[4.5]decane hydrochloride (Description 61, 750 mg, 2.65 mmol) in ethanol (30 mL) and the mixture was shaken under hydrogen (50 psi) for 24 hours. The mixture was filtered through Celite™ and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (510 mg, 99%). m/z (ES+) 158 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>C(O)C>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NC1CC1
Temperature: 80 °C
Yield: 96.2 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (0.50 g, 3.5 mmol) in ethanol was added cyclopropyl amine (0.60 g, 10.5 mmol). The solution was heated to 80° C. overnight and concentrated. The residue was purified by biotage column chromatography to give N-cyclopropyl-2-nitroaniline (0.60 g)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([C:19]2[C:20]([NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]3)=[CH:21][C:22]([NH:25][C:26]3[CH:31]=[N:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[N:23][CH:24]=2)[CH:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:32]([C:29]1[N:30]=[CH:31][C:26]([NH:25][C:22]2[N:23]=[CH:24][C:19]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH2:10][CH2:9][OH:8])=[O:13])=[CH:15]3)=[C:20]([NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]3)[CH:21]=2)=[N:27][CH:28]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)NCCO[Si](C)(C)C(C)(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(C(=O)NCCO)c3)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 0.118 mmol) was dissolved in THF (2 mL) and tetrabutylammonium fluoride on silica (1.5 mmol/g; 237 mg, 0.355 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol (1 mL) and absorbed on to a TsOH solidphase extraction cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The eluent was evaporated to dryness and the residue was purified by HPLC to give 1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH:30]([CH3:33])[NH:29][C:28]1=[O:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH:30]([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:34])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1NC(=O)N(C)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3C)nc2)CC1
Yield: 11.6 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 144 and 3,5-dimethylimidazolidine-2,4-dione (64 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Example 536, the title compound (13 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1.Br[CH2:34][C:35]([NH:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)[C:21]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]3[N:19]=2)=[CH:4][C:5]([C:15]#[N:16])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:10][C:9]1=[O:14]
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCNCC2=O)c1
Reactant: CNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 628)(20 mg, 0.045 mmol) in DMF (0.5 mL) was added 2-bromo-N-methylacetamide (13.54 mg, 0.089 mmol) followed by K2CO3 (73.9 mg, 0.535 mmol) at room temperature and stirred at room temperature for 1 h, LC-MS indicated completion. Purification via preparative HPLC gave the title compound as a yellow solid (5.9 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:17]2[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CCCCCCCCCCCCCc1nc2cnccc2n1-c1ccccc1
Yield: 33.9 %

Procedure:
Method B applied to 4-chloro-3-nitropyridine (79 mg, 0.5 mmol) and tetradecanoic acid phenylamide (182 mg, 0.6 mmol) afforded the title compound as viscous oil (64 mg, 34%). 1H NMR (DMSO) δ 0.83 (t, J=6.7Hz, 3H), 1.16-1.32 (m, 20H), 1.73 (p, J=6.7 Hz, 2H), 2.83 (t, J=6.7Hz, 2H). 7.63-7.71 (m, 6H), 8.56 (d, J=5.2Hz, 1H), 9.43 (s, 1H).
Reaction SMILES: Br[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:27][C:28]1[C:29]([OH:35])=[N:30][CH:31]=[N:32][C:33]=1[NH2:34].Cl>CCO>[NH2:34][C:33]1[C:28]2[N:27]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]4)[CH2:14][CH2:13][CH2:12]5)=[CH:7][CH:6]=3)[C:2]([CH3:26])([CH3:25])[O:35][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: Nc1ncnc(O)c1N
Reactant: COC(=O)CC12CCCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Agent: Cl
Solvent: CCO
Product: COC(=O)CC12CCCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of methyl {5-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[3.2.2]non-1-yl}acetate (Intermediate 24; 80 mg, 0.19 mmol) in absolute EtOH (20 mL) was added 5,6-diaminopyrimidin-4-ol (30 mg, 0.21 mmol) followed by 1M HCl (0.21 mL). The suspension was heated under gentle reflux (80° C.) overnight then allowed to cool, the solvent removed and the residue treated with 2M NaOH (2 mL). The aqueous phase was extracted into EtOAc (3×50mL), the organic extracts were combined, dried (MgSO4) and concentrated to leave a pale yellow gum. This was purified on a 12 g Crawford silicycle cartridge, loading in DCM and eluting with 0-5-10% MeOH-DCM, giving the title compound as a pale yellow gum (55 mg, 0.123 mmol, 65%); 1H NMR (CDCl3) 1.41-1.61 (14H, m), 1.71 (6H, s), 2.07 (2H, s), 3.61 (3H, s), 7.11 (2H, d), 7.51 (2H, d), 8.14 (1H, s); MS m/e MH+ 449.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH2:26]([S:38][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C

Procedure:
To a 3-liter three-necked flask equipped with stirrer, thermometer, nitrogen inlet and distillation set-up are charged 357.8 g (1 mole) of 5-chloro-(2-hydroxy-3,5-di-tert-butyl-phenyl)-2H-benzotriazole, available from CIBA-GEIGY Corp. as TINUVIN® 327, 216.8 g (1.05 mole) of n-dodecyl mercaptan and 600 mL of N,N-dimethylformamide (DMF). Then 73.9 g (0.54 moles) of potassium carbonate and 2 g of potassium iodide are added and the mixture heated for 20 hours at 150° C. under a nitrogen atmosphere. Any water which is liberated as a result of the reaction distills off as an azeotrope until the head-temperature reaches 132° C. After 20 hours at 150° C. the starting 2H-benzotriazole is totally consumed. With partial vacuum at 80°-100° C., most of the DMF is distilled off. To the resulting oil is added at 80° C. 1 L of toluene and 500 mL of water. The aqueous phase is drained off. The toluene solution is washed twice more with 500 mL water containing 1 mL of acetic acid. The organic solution is freed from residual water by azeotropic distillation until a clear solution is obtained. Under partial vacuum all but about 100 mL of toluene is distilled off at 70° C. The residue is diluted at 60° C. with 2 L of isopropanol and some product seeds are added The product gradually crystallizes and the mixture is slowly cooled to 10° C. The product is filtered off and washed with 300 mL of isopropanol to yield 490.4 g (93.6% of theory) of the title compound, mp. 62°-64° C.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([NH:9][C:13](=[O:14])/[CH:12]=[CH:11]\[S:10][C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCCCn1sccc1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)/C=C\SC(=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.), stirred solution of 2.0 g (0.0094 mol) of 2-octyl-4-isothiazolin-3-one in 50 ml of anhydrous tetrahydrofuran under nitrogen was added dropwise 2.82 ml (0.0028 mol) of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran over a 20 min. period. After the addition the mixture was stirred at -78° C. for 1 hr. Over a 15 min period 1.24 ml (0.0094 mol) of phenylacetyl chloride was added. After this addition the mixture was allowed to warm to room temperature. After 12 hr the reaction mixture was a white solid suspended in an orange solution. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed once with aqueous saturated sodium bicarbonate solution. The organic layer was set aside and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed once with water, with brine, and dried over anhydrous magnesium sulfate. Filtration and removal of solvents gave N-octyl-cis-3 -(phenylacetylthio)acrylamide as an oil which crystallized upon standing to give 3.0 g (96% yield) of a white solid whose NMR is reported in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].O.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: CCC(CC)CC1CC(c2onc(C(CC(=O)Nc3ccc(C)cc3Cl)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)CC1CC(c2onc(C(CC(=O)O)CC(=O)Nc3ccc(C)cc3Cl)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}butanoate (122 mg) and water (0.7 mL) were mixed. To the mixture was added a solution of 25 w/w % hydrogen bromide in acetic acid (1.4 mL) at ice temperature. After stirring at RT for 2 hr, aqueous 4 N sodium hydroxide (1.65 mL) was added to the reaction mixture at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform/acetic acid=1/20/0.1) to give the title compound (56.7 mg). The title compound was analyzed using a chiral column. The retention time of the title compound was 8.2 min., and the optical purity thereof was 90.5% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[CH3:18][N:19]=[C:20]=[S:21].O>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3ccc(N)cc3)nc2c1
Reactant: CN=C=S
Solvent: O
Solvent: CS(C)=O
Product: CNC(=S)Nc1ccc(-c2cn3ccc(C)cc3n2)cc1
Yield: 81.9 %

Procedure:
A solution of 7-methyl-2-(4-aminophenyl)imidazo-[1,2-a]pyridine (14.9 g) and methyl isothiocyanate (6.4 g) in dimethyl sulfoxide (400 ml) was stirred at 50° C. for 10 hours. The reaction mixture was poured into water (1 l) and the resultant precipitate was collected by filtration, washed with water and ethyl acetate successively and dried over phosphorus pentoxide to give 7-methyl-2-[4-(3-methylthioureido)-phenyl]imidazo[1,2-a]pyridine (16.2 g).
Reaction SMILES: [CH2:1]([C:7]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([OH:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:9]=2[O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH2:22]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([O:21][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:17][C:18]([CH3:20])=[CH:19][C:9]=2[O:8]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cc(C)cc(OC(=O)CCCN3CCCC3)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno [2,3-c][1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: C[Si](C)(C)[Cl:3].N[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[N:17]2)[N:8]=1>ClCCl.N([O-])=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[N:17]2)[N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=N[O-]
Solvent: ClCCl
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2noc(Cl)n2)c1

Procedure:
37.2 1.14 ml (9.00 mmol) of trimethylchlorosilane are added to a suspension of 381 mg (1.00 mmol) of 2-[3-(5-amino-1,2,4-oxadiazol-3-yl)-benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one in 5 ml of dichloromethane. A solution of 865 mg (3.00 mmol) of tetrabutylammonium nitrite in 3 ml of dichloromethane is slowly added dropwise to this suspension at room temperature with stirring. After the reaction mixture has been stirred at room temperature for 16 hours, it is filtered. The filtrate is partitioned between dilute sodium hydrogencarbonate solution and dichloromethane. The organic phase is dried over sodium sulfate and evaporated, giving crude 2-[3-(5-chloro-1,2,4-oxadiazol-3-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one as yellowish oil, which is employed for the next reaction without further purification; ESI 401.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 60 °C
Yield: 9.7 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (185 mg, 0.05 eq.), (R)-BINAP (442 mg, 0.05 eq.) and 4-fluoro-phenylboronic acid (4.87 g, 2.5 eq.). 300 mL of MeOH and 30 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (2.8 g). The reaction mixture was heated at 60° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.40 g (10%) of the title product as a light yellow oil. ES-MS m/e: 298.2 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][C@H:3]1[OH:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]>ClCCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:4][C@H:3]2[OH:22])[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reactant: O=Cc1cnc(CO)c(Cl)c1
Solvent: ClCCCl
Solvent: CO
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@H](NCc2cnc(CO)c(Cl)c2)[C@H](O)C1

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 31 as a free base: 60 mg, 0.196 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 33.6 mg, 0.196 mmol) in DCE (5 ml) and Methanol (0.5 ml) was stirred at rt for 5 h. LCMS showed desired compound Rt 2.16 [M+H]+ 460 and not starting material, sodium triacetoxy borohydride (125 mg, 0.588 mmol) was added. The mixture was stirred under nitrogen at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (62.3 mg, 0.294 mmol) was added. The mixture was stirred at room temperature for 3 h. Full conversion to the amine was observed by LCMS desired compound Rt 2.02 [M+H]+ 462. It was quenched with saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), filtered, and concentrated affording 78.5 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (35 mg, 0.072 mmol, 36.8% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=[O:19].N1C=CC=CC=1.Cl>C(OCC)C>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:21][NH:20][C:18](=[O:19])[C:17]([F:23])([F:22])[F:16])=[O:8])([O-:3])=[O:2]
Reactant: NNC(=O)C(F)(F)F
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)F
Reaction time: 0.05 h

Procedure:
To 1.65 g (0.007 mole) of 4,4,4-trinitrobutyryl chloride in 15 mL of anhydrous diethyl ether stirred in a water bath at 15° C. was added 0.9 g (0.007 mole) of N-(trifluoroacetyl)hydrazine. Pyridine (0.6 mL, 0.007 mole) was added dropwise. After 3 minutes, dilute hydrochloric acid was added and the ether layer was separated and dried (Na2SO4). The volatiles were removed and the residue was stirred with water and then with CH2Cl2 to give the product N-(4,4,4-trinitrobutyryl)-N'-(trifluoroacetyl)hydrazine, 1.15 g (50%), mp 154°-156° C. Crystallization from 1,2-dichloroethane raised the melting point to 157°-159° C.; 1H NMR (acetone-d6 +D2O): 2.97 (t, 2H), 3.86 (t, 2H); IR (KBr): 3330, 3220 (NH), 1745, 1690 (C=O); 1610, 1590 (NO2); 1195 (C--F).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 1-chloro-isoquinoline (1.00 g, 6.11 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.34 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 4 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.83 g (42%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.42-1.54 (m, 2H), 1.43 (s, 9H), 1.92-1.93 (m, 2H), 2.89 (br s, 2H), 3.97-4.03 (m, 2H), 4.29-4.35 (m, 1H), 6.88 (d, J=5.8 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.0 Hz, 1H), 7.63 (t, J=7.0 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.86 (d, J=5.8 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 28.09, 31.42, 42.99, 47.39, 78.50, 109.41, 117.77, 123.10, 125.29, 126.38, 129.60, 136.67, 141.31, 153.91, 154.49. MS (ISP): 328.5 [M+H]30.