Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:16]([F:15])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)cc1F
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(F)c3)nc2n(CC)c1=O
Yield: 43.6 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.72 g (13.9 mmol) of 3-fluoro-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.97 g (yield 44%) of Compound 172 as pale yellow flocculent precipitates.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]12[C:18](=[O:19])[O:17][C:15](=[O:16])[C:11]=1[CH2:12][CH2:13][CH2:14]2.Cl>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:18]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]([OH:17])=[O:16])=[O:19])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1cccn1N
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccn1NC(=O)C1=C(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
1-Amino-1H-pyrrole-2-carboxamide (91 mg, 0.724 mmol) was dissolved in THF (3 mL), then 1-cyclopentene-1,2-dicarboxylic anhydride (100 mg, 0.724 mmol) was added. The reaction was stirred at rt for 30 min, then 0.5 M HCl (10 mL) was added. The precipitated product was filtered, rinsing with more 0.5 M HCl. The solids were dried to give 19A (177 mg, 92%). 19A had an analytical HPLC retention time=1.597 min (Phenomenex Luna 4.6×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=264.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[Cl:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(Cl)c3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (52%) which was obtained as an off-white solid. MS: m/e=359.4 [M+H]+. To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (84%) which was obtained as a white solid. MS: m/e=343.4 [M−H]−.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]([C:41]1[CH:42]=[CH:43][C:44]([F:50])=[C:45](B(O)O)[CH:46]=1)#[N:40]>>[NH2:30][C:29]1[S:28][C:27]([C:43]2[CH:42]=[C:41]([C:39]#[N:40])[CH:46]=[CH:45][C:44]=2[F:50])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(C#N)ccc3F)sc2N)c1N1CCC(CN)CC1
Yield: 35 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-cyano-2-fluorophenylboronic acid gave 298 as a yellow solid (32 mg, 35% over two steps). 1H NMR (400 MHz, d4-MeOD) 8.75 (dd, J=6.9, 2.2 Hz, 1H), 7.80-7.75 (m, 1H), 7.51-7.45 (m, 2H), 3.74 (s, 3H), 3.25-3.11 (m, 4H), 2.60 (d, J=6.6 Hz, 2H), 1.87 (d, J=12.5 Hz, 2H), 1.53-1.49 (m, 1H), 1.43-1.32 (m, 2H). LCMS (ES+) m/z 455 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH:11]([OH:16])[CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([OH:16])[CH2:12][C:13](=[O:14])[NH:19][N:20]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1c(Cl)cc(C(=O)C(O)CC(=O)O)cc1Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc(C2=NNC(=O)CC2O)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixture of 2.77 g of 4-(3,5-dichloro-4-methylphenyl)-3-hydroxy-4-oxobutyric acid (prepared as described in Preparation 1), 0.5 g of hydrazine hydrate (100%) and 20 ml of ethanol was stirred at room temperature for 6 hours. The resulting white powder was then collected by filtration, to give 1.77 g (yield 65%) of the desired Compound No. 7, melting at 253°-256° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][S:23]([C:26]1[CH:31]=[C:30]([C:2]2[S:6][C:5]([C:7]3[N:11]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(-c2ccc(Br)s2)n(-c2ccncc2)n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccncc2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
A mixture of methyl 5-(5-bromothiophen-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (480 mg, 1.3 mmol) and 3-(methylsulfonyl)phenylboronic acid (390 mg, 1.9 mmol) was suspended in THF (6 mL) with Na2CO3 (1.0 mL of a 2M aqueous solution, 2.0 mmol). The mixture was sparged with nitrogen for ˜10 minutes, treated with Pd(PPh3)4 (54 mg, 47 mol), and heated to 65° C. After 4 hours at 65° C. there was still starting methyl 5-(5-bromothiophen-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate visible as evidenced by LC/MS. Additional palladium catalyst was added and heating was continued. After heating at 65° C. overnight the reaction mixture was concentrated under reduced pressure to afford a dark semi-solid that was triturated with EtOAc and filtered to remove the solids. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 0% to 50% MeCN/CH2Cl2 to afford methyl 5-(5-(3-(methylsulfonyl)phenyl)-thiophen-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (137 mg, 24% yield) as a mixture with triphenylphosphine oxide. This colorless film will be carried on to the Grignard addition without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C12BC(CCC1)CCC2.C1C[O:30]CC1>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:15][OH:30])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: C=C1c2ccccc2C=Cc2cc(Br)ccc21
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-5-methylene-dibenzo[a,d]cycloheptene (5.7 g) in dry THF (20 ml), under an inert atmosphere, was added 9-borabicyclo[3,3,1]nonane (4.4 ml of a 0.5 molar solution in THF) at ambient temperature, and the reaction mixture was then refluxed for 3 h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (100 ml) and 30% hydrogen peroxide (20 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 h period then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×100 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent to give the title compound (6.0 g) as a colourless oil. δ (360 MHz, CDCl3) 3.81 (2H, d, J=7.9 Hz, CH--CH2OH), 4.17 (1H, t, J=7.9 Hz, CH--CH2OH), 6.75 (1H, d, J=12 Hz, CHA =CHB), 6.89 (1H, d, J=12 Hz, CHA =CHB), 7.15-7.48 (7H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-n2cccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(-n2cccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 1-(4-hydroxyphenyl)pyrrole (0.8 g), potassium carbonate (3.2 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (10 mL) affords 1.37 g of 1-[4-(3-chloropropoxy)phenyl]pyrrole as a brown solid used without further purification.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 120 °C

Procedure:
A screw cap test tube was charged with n-heptanol (283 μL, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), 1,10-phenanthroline (90.1 mg, 0.500 mmol), Cs2CO3 (977 mg, 3.00 mmol) and solvent (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 120° C. for 40 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[CH2:18]([O:20][CH2:21]Cl)[CH3:19]>ClCCl>[CH2:18]([O:20][CH2:21][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=1)[CH3:19]
Reactant: CCOCCl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCOC(=O)c1ccc(O)cc1

Procedure:
36.7 ml (0.26 mole) Of triethylamine were added under a nitrogen atmosphere to a solution of 36.1 g (0.26 mole) of 4-hydroxybenzoic acid in 200 ml of dichloromethane. The mixture was cooled in an ice-water bath, and 24.5 ml (0.26 mole) of chloromethyl ethyl ether in 100 ml of dichloromethane were added dropwise.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17]([NH:31][CH2:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: NCC1CCCCC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (25 mg, 0.072 mmol, 1.0 eq) in DMF (5004), was added cyclohexylmethylamine (18.7 μL, 0.144 mmol, 2.0 eq) and reaction was stirred at 70° C. overnight. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=397.1
Reaction SMILES: [ClH:1].[N:2]1([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17](=[O:27])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:26])[CH2:12][CH2:11]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(Cl)[Cl:36]>O1CCCC1>[ClH:36].[ClH:1].[N:2]1([CH2:7][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17](=[O:27])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:26])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc2cc(N3CCN(CC(=O)N4CCCC4)CC3)c(=O)[nH]c12
Reactant: ClCCl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2cc(N3CCN(CCN4CCCC4)CC3)c(=O)[nH]c12

Procedure:
2.0 Grams of 3-[4-(1-pyrrolidinylcarbonylmethyl)-1-piperazinyl]-8-methylcarbostyril hydrochloride was suspended in 20 ml of tetrahydrofuran, to this suspension was added dropwise a solution of 0.32 g of lithium aluminium hydride in 20 ml of tetrahydrofuran under nitrogen gas stream with stirring. This reaction mixture was stirred at the same temperature for 30 minutes, then the reaction mixture was refluxed by heating on a oil bath for 2 hours. To the reaction mixture was added water and methylene chloride and filtered with Celite (a trademark for diatomaceous earth product, manufactured by Johns Manville Sales Corp., U.S.A.). The filtrate was extracted with methylene chloride, washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous sodium sulfate, then concentrated by removing the solvent under reduced pressure, the residue thus obtained was purified by a silica gel column chromatography (eluent: methylene chloride:methanol=10:1). The desired product was converted into dihydrochloride by using ethanol-HCl, then recrystallized from ethanol-water to obtain 1.15 g of 3-{4-[2-(1-pyrrolidinyl)ethyl]-1 -piperazinyl}-8-methylcarbostyril dihydrochloride. Light yellow needle-like crystals. Melting point: over 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])=[O:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[N:47]=[CH:48]C=CC=2N=N1.Cl.CNC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:25])([CH3:26])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:33])([CH3:34])[C:30]([N:47]([CH3:48])[CH3:46])=[O:31])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccn2c(C(=O)c3ccc(Cl)cc3)c(CC(C)(C)C(=O)O)c(C(=O)C(C)(C)C)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccn2c(C(=O)c3ccc(Cl)cc3)c(CC(C)(C)C(=O)N(C)C)c(C(=O)C(C)(C)C)c2c1
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a solution of 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoic acid (100 mg, 0.207 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (157.7 mg, 0.415 mmol), and dimethylamine-HCl (18.6 mg, 0.228 mmol) is added TEA (0.173 mL, 1.245 mmol). The reaction is stirred for 16 h then purified by HPLC to give the title compound (36 mg, 34%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:33])[NH:9][C:10]([CH3:32])([CH3:31])[CH2:11][C:12](=[O:30])[NH:13][CH:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][C:24]3[C:29]([C:17]=2[CH2:16][CH2:15]1)=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH3:6])([CH3:5])[CH3:4].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[N:52]([C:53]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:51]=[N:50][N:49]=2)=[CH:38][CH:37]=1.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C.O>[C:3]([O:7][C:8](=[O:33])[NH:9][C:10]([CH3:32])([CH3:31])[CH2:11][C:12](=[O:30])[NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[N:51]=[N:50][N:49]=3)=[CH:40][CH:41]=2)[C:18]2[CH:22]=[CH:23][C:24]3[C:29]([C:17]=2[CH2:16][CH2:15]1)=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(CC(=O)NC1CCc2c(ccc3ccccc23)NC1=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)NC1CCc2c(ccc3ccccc23)N(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C1=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A solution of dry powdered potassium hydroxide (0.23 g, 4.0 mmol) and (1,1-dimethyl-2-(4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepin-3-ylcarbamoyl)ethyl)carbamic acid tert-butyl ester (0.49 g, 1.0 mmol) in DMSO (15 ml) was stirred for 0.5 h under an atmosphere of nitrogen. 5-(4'-Bromomethyl-biphenyl-2-yl)-N-(triphenylmethyl)tetrazole (0.59 g, 1.1 mmol) was added and the mixture was stirred for 1 h. A 10% aqueous solution of ammoniumchloride (30 ml), water (100 ml) and ethyl acetate (60 ml) were added and the phases were separated. The organic layer was dried (MgSO4), and the solvent was evaporated in vacuo. Purification by columm chromatography on silica gel (100 g) using heptane and ethyl acetate (2:3) as eluent afforded 0.45 g of (1, 1-dimethyl-2-(4-oxo-5-(2'-(N -triphenylmethyltetrazol-5-yl)biphenyl-4-ylmethyl)-2,3,4,5-tetrahydro- 1H-naphtho[2,1-b]azepin-3-ylcarbamoyl)ethyl)- carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[OH:34][C:32]([CH3:35])([CH3:33])[CH2:31][N:28]1[CH:29]=[CH:30][C:26]([NH:25][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:27]1
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)CC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 45 %

Procedure:
Using the method described in Example 17, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.63 g, 45%); ES+-HRMS m/e calcd for C23H27N5O4F2 [M+H+] 476.2104 found 476.2104. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H) 0.89 (d, J=6.6 Hz, 3H) 1.05 (s, 3H) 1.07 (s, 3H) 1.44 (br s, 1H) 1.73-1.86 (m, 1H) 2.11-2.27 (m, 1H) 3.89 (s, 2H) 4.67 (s, 1H) 5.53 (dd, J=11.2, 4.4 Hz, 1H) 6.04 (d, J=3.0 Hz, 1H) 6.40 (d, J=2.3 Hz, 1H) 7.34-7.44 (m, 2H) 7.44-7.52 (m, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.28 (d, J=3.0 Hz, 1H) 10.85 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([CH2:21][C:22]#[N:23])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:4][CH2:3]1>CO.[Pd]>[NH2:15][C:14]1[C:9]([NH:8][CH:5]2[CH2:6][CH2:7][C:2]([CH2:21][C:22]#[N:23])([OH:1])[CH2:3][CH2:4]2)=[C:10]2[S:20][CH:19]=[CH:18][C:11]2=[N:12][CH:13]=1
Reactant: N#CCC1(O)CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: N#CCC1(O)CCC(Nc2c(N)cnc3ccsc23)CC1
Reaction time: 2 h

Procedure:
A mixture of {1-hydroxy-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (0.11 g, 0.33 mmol) and 10% Pd/C (0.050 g) in methanol (7 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The mixture was filtered, concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product as a mixture of cis- and trans-isomer mixtures (38 mg, 38%). LCMS calculated for C15H19N4OS (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC[C@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 92 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 13b as the starting material afforded the title compound (44 mg, 92% yield) as a white solid: