Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18](O)=[O:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.81 g, 9.7 mmol), 3-fluoro-4-methylbenzoic acid (1.50 g, 9.7 mmol), and triethylamine (6.8 mL, 49 mmol) in acetnitrile (30 mL), HBTU (4.06 g, 10.7 mmol) was added. After stirring at rt for 1 h, the mixture was poured onto water (150 mL), and the mixture was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (4:1-2:1) to give 3.14 g (quant) of the title compound as a white solid.
Reaction SMILES: O.[N+:2]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 3.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 35.0 g of 1,6-bis(4-(4-nitrobenzyl)phenyl)hexane in 200 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a mixed solvent of toluene and denatured ethanol, to obtain 26.1 g of 1,6-bis(4-(4-aminobenzyl)phenyl)hexane. Melting point was from 111.4° to 112.2° C.
Reaction SMILES: [CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=O)[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH2:25]([Li])CCC.O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=[CH2:25])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCC1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC(CC)[C@@H]34)[C@@]2(CO)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.7 g of 15-alpha-ethyl-19-hydroxy-4-androstene-3,17-dione in 25 ml of tetrahydrofuran is instilled in a suspension of 28.6 of methyl triphenylphosphonium bromide in 200 ml of tetrahydrofuran, which was stirred with 200 ml of butyllithium solution (1.6 m in ether) for 1.5 hours at 20° C., and stirred for one hour at 20° C. Then it is mixed with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and is freed from the solvent in a vacuum. After chromatographic purification on silica gel with hexane/ethyl acetate, 1.95 g of pure 15-alpha-ethyl-3-methylene-19-hydroxy-4-androsten-17-one is obtained as foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]4[NH:22][C:23]5[C:28]([CH:29]=4)=[C:27](Br)[CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:14][CH2:13]3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]4[NH:22][C:23]5[C:28]([CH:29]=4)=[C:27]([C:36]4[CH:37]=[N:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:14][CH2:13]3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NC1CCN(CCN2C3CCC2CC(O)C3)CC1)c1cc2c(Br)cccc2[nH]1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5C6CCC5CC(O)C6)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 197 (see example 175) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cnc2ccccc2n1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cnc2ccccc2n1
Yield: 76 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloroquinoxaline instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 118 mg, 76%) which was obtained as a light yellow solid. MS: m/e=312.2 [M+H]+.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (60 mg, 216 μmol) prepared in Preparation 6 in THF (8 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (539 μl, 539 μmol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (1.08 mL, 539 μmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (270 μl, 270 μmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (0.54 mL, 270 μmol) were added. The reaction mixture was then stirred at room temperature for 18 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 1-18% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (75 mg, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([Sn]=O)CCC.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CCCC[Sn]=O
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Octadecyl 3-(3,5-di-tertbutyl-4-hydroxyphenyl)-propionate was prepared from 124.8 g (0.427 mole) of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, 88.8 g (0.328 mole) of octadecyl alcohol and 0.13 g (0.0007 mole) of monobutyltin oxide. To the solution (214 g) of it was added 35 g of synthetic magnesium silicate (manufactured by Mizusawa Chemical Co.), and the solution was stirred at 60° C. for 0.5 hour. The organic layer wa separated by filtration. The residual tin content was 3 ppm (removal rate: 99.2%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1C=CC=CC=1.CN(C)C=O>[O:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCOc1ccccc1
Reactant: C=CC(N)=O
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C=CC(=O)NCCCCOc1ccccc1
Yield: 81.7 %

Procedure:
Added to 20 ml of N,N-dimethylformamide were 1.34 g of acrylic amide and 3.4 g of (4-bromobutoxy)benzene. With stirring, 0.88 g of flaky potassium hydroxide which had been ground in a mortar was added. Phenothiazine was added in an amount of 0.5% based on the acrylic amide. After they were reacted at 0°-5° C. for 6 hours, insoluble matter was filtered off from the liquid reaction mixture. The solvent and unreacted raw materials were distilled off from the filtrate. The residue was extracted with benzene-water, thereby obtaining the intended product in the benzene layer. Benzene was then driven off from the benzene layer to obtain 2.66 g of N-(4-phenoxybutyl)acrylic amide (yield: 81%). It was purified further with column chromatography in which silica gel and benzene were used as an adsorbent and developer respectively. Its melting point was measured and its elementary analysis was also conducted. The following results were obtained. Melting point: 46°-47° C. Elementary analysis data: C, 71.29% (Calculated: 71.19%); H, 7.31% (7.82%); N, 6.15% (6.38%).
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]2[C:9](C=C3[C:16]=1[C:15](C#C)=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>CO.[OH-].[K+].O>[C:22]([C:21]1[C:25]2[C:16]([CH:3]=[C:4]3[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[CH:23]
Reactant: C1CCOC1
Reactant: C#Cc1cccc2cc3ccccc3c([Si](C)(C)C)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
27 g (0.098 mol) of 9-trimethylsilyl ethynyl anthracene was put into a 1 L round-bottomed flask equipped with a stirrer and dissolved in a mixture of 100 ml of THF and 200 ml of methanol. A solution in which 0.7 g of KOH was dissolved in 7 ml of water was dropped into the resulting solution. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, THF and methanol were removed under a reduced pressure. The reaction mixture was then extracted with methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain yellow viscous liquid, which was then purified by silica gel column chromatography using hexane as an eluent, to give 17 g (85.8% yield) of the desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24])([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[S:24][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)([CH3:12])[CH3:11]
Reactant: NC1(CCl)CCCC1
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: CC(C)c1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl>CCCCCC>[CH3:10][C:2]([O:1][Si:22]([CH3:25])([CH3:24])[CH3:21])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)CCOC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C)(CCOC)O[Si](C)(C)C

Procedure:
To a solution of 13 g. (0.091 moles) of 4-hydroxy-4-methyl-7-oxa-1-octyne and 16 g. (0.235 moles) of imidazole in 80 ml. of dry dimethylformamide is added dropwise, at 5° C. under nitrogen with stirring, 12.5 ml. (0.115 moles) of trimethylchlorosilane. After an additional 15 minutes at 5° C. the solution is stirred at ambient temperature for 18 hours then added to 450 ml. of hexane. The resulting solution is washed with ice-cold water, ice-cold saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness in vacuo. Distillation of the residual oil furnishes 16.8 g. (86%) of product; b.p. 87°-88° C. (7 mm.).
Reaction SMILES: Br[C:2]1[C:3]([NH2:19])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C([O-])([O-])=O.[Na+].[Na+].CC#N>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.O>[NH2:19][C:3]1[C:2]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C:21](=[O:20])[NH:22][CH2:23][CH2:24]3)=[CH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: CCS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Reactant: O=C1NCCc2cc(B(O)O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
A mixture of the 3-bromo-5-(4-(ethylsulfonyl)phenyl)pyridin-2-amine (100 mg, 0.29 mmol), 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (75 mg, 0.29 mmol), PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) and Na2CO3 in 3:1 MeCN:H2O was microwave heated at 150° C. for 3 min. At completion, the reaction mixture was filtered, then purified by preparatory HPLC to provide 6-(2-amino-5-(4-(ethylsulfonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one as a pale yellow solid (48 mg, 41% yield) after reverse phase preparatory HPLC purification. 1H NMR (400 MHz, MeOD) δ ppm 8.37 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 3.56 (t, J=6.7 Hz, 2H), 3.19-3.27 (m, 2H), 3.07 (q, J=6.5 Hz, 2H), 1.25 (t, J=7.3 Hz, 3 H); MS (EI) m/z: 408 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[C:26]([C:27]([O:29][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 50 °C
Yield: 49.5 %

Procedure:
Triethylamine (20 ml) and 3-bromophthalide (21.3 g) were added to a suspension of 2(3'-trifluormethylanilino)-nicotinic acid (28,2 g in 500 ml of acetone). The mixture was refluxed during 4 hours. The obtained greenish yellow suspension was poured into 6000 ml of water, which was previously heated at 50° C. The stirred reaction mixture was cooled to 5° C., and the formed precipitate was filtered and washed with cool water. Yield: 52% (20.5 g) of phthalidyl 2-(3'-trifluormethylanilino)-pyridin-3-carboxylate, m.p: 162°-164° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20](F)[C:19]([F:24])=[C:18]([F:25])[N:17]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:37]=[CH:36][C:34]([O-:35])=[CH:33][C:32]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O-:30])=[O:29].[K+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:28]([C:31]1[CH:37]=[CH:36][C:34]([O:35][C:20]2[C:19]([F:24])=[C:18]([F:25])[N:17]=[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:27][CH:26]=3)[C:21]=2[F:22])=[CH:33][C:32]=1[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc([O-])cc1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(F)c2F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
40 g of the 2-(4-benzyloxycarbonylphenoxy)-3,4,5,6-tetrafluoropyridine (0.106 mol) prepared as described in Example 6 and 30 g of potassium 4-nitro-3-benzyloxyphenoxide (0.106 mol) are dissolved in 500 ml of dimethyl sulfoxide. 30 g of potassium carbonate (0.22 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours, then heated at 60° C. for 24 hours, and 15 g of potassium hydrogencarbonate (0.15 mol) are then added. The reaction solution is then cooled to room temperature and filtered through a fluted filter. The crude product is extracted by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([N:14]3[CH2:18][CH2:17][C@@:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([N:14]3[CH2:18][CH2:17][C@@:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(CO)cc4)CC3)C2)c2ccccc21
Reactant: Oc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(COc5ccccn5)cc4)CC3)C2)c2ccccc21
Reaction time: 8 h

Procedure:
To a mixture of (1R)-1′-({1-[4-(hydroxymethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (16.0 mg, 0.0000440 mol, prepared in example 237), triphenylphosphine (17 mg, 0.000066 mol), and 2-hydroxypyridine (4.0 mg) in tetrahydrofuran (2 mL, 0.02 mol) was added diisopropyl azodicarboxylate (14 μL, 0.000070 mol) at room temperature, and the mixture was stirred overnight. The product was isolated and purified by prep-HPLC. LC-MS: 441.2 (M+H+)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([O:10]CC)=O)[C:4](=[O:13])[CH2:3]1.[NH2:14][CH2:15][C:16]([NH2:18])=[O:17]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:10])[C:4](=[O:13])[CH2:3]1
Reactant: NCC(N)=O
Reactant: CCOC(=O)CN1CC(O)CC1=O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (0.5 g) and glycinamide (0.6 g) was stirred under nitrogen at 80° C. for 4 hours. After cooling, the mixture was chromatographed on a silica gel column, by eluting with dichloromethane/methanol 7:3, affording the title compound (250 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O>[N+:12]([C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:18](=[O:20])[CH3:19])([O-:14])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CCCCN(C(C)=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A stirred suspension of N-n-butyl-3,5-dinitroaniline (5.5 g.) in acetic anhydride (20 ml.) was treated with a few drops of concentrated sulphuric acid and then heated on the steam bath for 3 hours. The cooled reaction mixture was added to ice-water (400 ml.) and the product was extracted with ethyl acetate (3 × 100 ml.). The combined organic extract was washed with 2N aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulphate, and the solvent removed in vacuo, to give 3',5'-dinitro-N-n-butylacetanilide (2.8 g.), in the form of an amber syrup, ν1670 cm-1.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:26][C:23]3([CH3:22])[CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(N)CC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2(C)CC2)cn1
Yield: 70 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methylcyclopropylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (83 mg, 70%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=342.3 [M−H]−.