Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.N1C=CC=CC=1.[Br:14][CH2:15][C:16](Br)=[O:17].O>C1(C)C=CC=CC=1>[Br:14][CH2:15][C:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(N)on1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)CBr)on1
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
To a solution of 5-amino-3-methylisoxazole (0.165 g, 1.67 mmol) in anhydrous toluene (6.5 ml) and anhydrous pyridine (0.18 ml, 2.0 mmol) cooled in an ice/water bath (T=˜10° C.) was slowly added bromoacetyl bromide (0.402 g, 2.0 mmol). The reaction mixture was stirred for 1.5 h under argon, then poured into water (20 ml), and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (30 ml), brine (30 ml), dried (Na2SO4), and concentrated in vacuo. The residue was triturated with diethyl ether, the precipitate was removed by filtration, and the filtrate was concentrated in vacuo to afford the title compound as a white solid (0.200 g, 55%); 1H-NMR (500 MHz, DMSO-d6) 2.18 (s, 3H, CH3), 4.08 (s, 2H, CH2Br), 6.15 (s, 1H, isoxazole C—H), 11.94 (s, 1H, CONH);
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)[CH:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([N:19]([CH:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[S:16]([C:13]2[CH:12]=[CH:11][C:10]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:15][CH:14]=2)(=[O:17])=[O:18])=[N:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: OCC1CCOCC1
Reactant: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (10.20 mg, 0.088 mmol) and 4-fluoro-N-(5-isopropylpyridin-2-yl)-N-(3-methylbutan-2-yl)benzenesulfonamide (32 mg, 0.088 mmol) in dimethyl sulfoxide (DMSO) (1 mL) stirred in air at room temperature was added sodium hydride (3.51 mg, 0.088 mmol, 60% wt in mineral oil). The reaction mixture was stirred at 20° C. for 2 hours. Additional (tetrahydro-2H-pyran-4-yl)methanol (10.20 mg, 0.088 mmol) and sodium hydride (3.51 mg, 0.088 mmol, 60% wt in mineral oil) were added and the reaction mixture stirred overnight. The reaction was carefully quenched with isopropanol (1 mL) and water (1 mL). The solvent was evaporated in vacuo and the residue partitioned between water (5 mL) and dichloromethane (2×5 mL), then separated using a hydrophobic frit. The solvent was removed in vacuo and the crude was purified by mass directed autoprep (formic acid modifier) to give the title product (32 mg). LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C@H:16]1[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:29]([CH2:39][OH:40])[O:28][C@@H:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@@H:17]1[N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:40][CH2:39][C@H:29]1[O:28][C@@H:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:17]([N:41]2[C:42](=[O:51])[C:43]3=[CH:50][CH:49]=[CH:48][CH:47]=[C:44]3[C:45]2=[O:46])[C@@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:30]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 20 h
Yield: 85 %

Procedure:
Under nitrogen gas atmosphere, acetic anhydride (200 ml) and DMAP (catalytic amount) were added to a solution of Compound 21 (10.5 g, 17.6 mmol) in pyridine (200 ml), and the mixture was stirred for 20 hours. Ethanol was added to the reaction mixture, and it was stirred for 20 minutes. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 22 (9.6 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[SH2:19].O>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)(=[S:19])[NH2:2]
Reactant: S
Reactant: N#Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccc(C(=O)O)cc1
Yield: 68 %

Procedure:
3 g of 4-cyanobenzoic acid 1 (20.4 mmol) were dissolved in 40 mL of pyridine and 2.1 mL of triethylamine (20.4 mmol) were added. Dry hydrogen sulphide was passed through the solution in a steady steam for 4 h. The mixture was then poured into water and the solid collected by filtration. Recrystallization from petroleum ether furnished 2.51 g of the pure compound 2 (68% yield).
Reaction SMILES: [Cl-].[F:2][C:3]1[C:28]([F:29])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:43][C:44]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O.O>C1COCC1.C1(C)C=CC=CC=1>[F:43][C:44]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][CH2:5][C:4]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:28]([F:29])[C:3]=1[F:2]
Reactant: CCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Reactant: O=Cc1cccc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Well-dried (2,3-difluoro-4-hexyloxybenzyl)triphenylphosphonium chloride (s-16) (7.5 g) and THF (100 ml) were mixed under an atmosphere of nitrogen, which was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.6 g) was added in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., 2,3-difluorobenzaldehyde (s-23) (1.9 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was poured into a mixture of water (100 ml) and toluene (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with water, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and the eluent was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of toluene (100 ml) and Solmix A-11 (100 ml), and Pd/C (0.1 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the completion of the reaction, Pd/C was removed, and the solvent was distilled off. The resulting residue was purified by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give 1-(2,3-difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g). The yield based on the compound (s-23) was 76.0%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[C:16]1=O)[CH2:22]2.[BH4-].[Na+]>CCO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:16]2[CH:17]3[CH2:23][CH:21]4[CH2:20][CH:19]([CH2:24][CH:15]2[CH2:22]4)[CH2:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC2C3CC4CC(C3)CC2C4)CC1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Ammonium formate (300 mg, 4.8 mmol) was added to a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in methanolic ammonia (2.5 mL) followed by 10% Pd/C (50 mg) and stirring was continued at room temperature overnight. The above mixture was filtered through celite, filtrate was collected, and concentrated under reduced pressure to furnish a crude residue. The residue was treated with 2N aqueous NaOH solution, extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to afford 200 mg (83% yield) of (4-amino-piperidine-1-carboxylic acid tert-butyl ester. Titanium isopropoxide (756 mg, 2.66 mmol) was added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (293 mg, 1.46 mmol) and adamantan-2-one (200 mg, 1.33 mmol) in EtOH (5 mL) and stirring was continued at room temperature overnight. NaBH4 (100 mg, 2.64 mmol) was added in portionwise and the resulting mixture was stirred at room temperature for 10 hrs. The reaction mixture was quenched with 2N aqueous NH3 solution and filtered. The filtrate was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 20% EtOAc in hexane as eluent) to afford 420 mg (94.4% Yield) of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3): δ 4.0 (s, 2H), 2.9-2.4 (m, 4H), 2.0-1.6 (m, 9H), 1.7 (s, 4H), 1.6-1.5 (d, 4H), 1.45 (s, 9H), 1.35-1.2 (m, 3H). A mixture of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 1.25 mmol) in dioxane.HCl (20 mL) was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue, which was washed with ether to afford 363 mg (93.8% Yield) of 4-(adamantan-2-ylamino)-piperidine dihydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 9.0 (s, 3H), 3.8 (s, 4H), 3.5-3.3 (m, 4H), 3.0-2.8 (m, 2H), 2.4 (d, 2H), 2.3 (d, 3H), 2.0 (t, 2H), 1.9-1.8 (m, 5H), 1.7 (s, 2H), 1.6-1.5 (d, 2H).
Reaction SMILES: [C:1]([C:3]([NH:6][S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])([CH3:5])[CH3:4])#[N:2].[CH3:12][SH:13].C(=O)([O-])[O-].[K+].[K+].CS.CO.Cl>CO>[C:1]([C:3]([NH:6][S:7]([CH2:10][CH2:11][S:13][CH3:12])(=[O:8])=[O:9])([CH3:5])[CH3:4])#[N:2]
Reactant: C=CS(=O)(=O)NC(C)(C)C#N
Reactant: CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CSCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8.2 g (0.0470 moles) N-(2-cyano-2-propyl)-vinylsulfonamide (the product of Example 26) in 30 ml methanol, 32 ml of a 1.5M solution of methanethiol was added over 5 minutes. A small amount (a few mg) of potassium carbonate was added to the mixture and it was stirred overnight at room temperature. The reaction mixture was warmed to about 30° C., more methanethiol/methanol solution (about 10 ml) was added, and the resulting mixture was stirred at 30° C. for four hours. The mixture was acidified with 10% hydrochloric acid and then evaporated to afford 10.0 g of a pale yellow oil. The oil was dissolved in methylene chloride, filtered and evaporated to dryness. The residue was purified by flash chromatography with 30% hexane in ethyl acetate to give 9.3 g of the above-identified product, as a colorless oil which crystallized upon standing.
Reaction SMILES: O1[CH:5]2[C:6]3[C:7]4[C:12]([C:13]5[C:18]([C:19]=3[CH:2]1[CH:3]=[CH:4]2)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[CH:9][CH:8]=4.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.BrC1C=CC=C(I)C=1.C(N(CC)CC)C>[Zn].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.C1(C)C=CC=CC=1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]=3[CH:14]=2)=[CH:23][CH:22]=1
Reactant: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Brc1cccc(I)c1
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Temperature: 110 °C
Yield: 62 %

Procedure:
Compound A (4.0 g, 16.4 mmol), zinc (10.72 g, 163.9 mmol), PdCl2(PPh3)2 (1.16 g, 1.7 mmol), and 1-bromo-4-iodobenzene (4.64 g, 16.4 mmol) or 1-bromo-3-iodobenzene were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried toluene (100 mL) and triethyl amine (23.0 mL, 165.9 mmol) were added to the bottle. The mixture in the bottle was heated to 110° C. for reaction for 24 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by chromatography with hexanes to obtain B (3.90 g, yield=62%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-5-methyl-2-hexanone (263.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.0001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-5-methylhexane (255.8 mg; yield: 96.4%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 7.7:1. The results of elementary analysis were as follows.
Reaction SMILES: [C:1]1([Si:7]([O:16][C:17]([CH3:19])=[O:18])([O:12][C:13]([CH3:15])=[O:14])[O:8][C:9]([CH3:11])=[O:10])C=CC=CC=1.C(CC[Si](OC(C)=O)(OC(C)=O)OC(C)=O)(F)(F)F>>[CH3:1][Si:7]([O:8][C:9]([CH3:11])=[O:10])([O:16][C:17]([CH3:19])=[O:18])[O:12][C:13]([CH3:15])=[O:14]
Reactant: CC(=O)O[Si](OC(C)=O)(OC(C)=O)c1ccccc1
Agent: CC(=O)O[Si](CCC(F)(F)F)(OC(C)=O)OC(C)=O
Product: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O

Procedure:
C6H5Si(OCOCH3)3; CF3CH2CH2Si(OCOCH3)3;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:24]=1.C[Al](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:24]=2)=[O:13])[N:3]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: COC(=O)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 120 °C
Yield: 31.1 %

Procedure:
To a stirred solution of 3-aminoisoquinoline (75 mg, 0.52 mmol) and 2-({2-[(morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester (149 mg, 0.40 mmol) in DCE (6 mL) at 0° C., under argon, was added trimethylaluminium (2M in toluene, 0.4 mL, 0.8 mmol). The reaction was heated at 120° C. (bath temperature) for 3 hours. On cooling the reaction was diluted with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash NH2 (Separtis) (Eluant: EtOAc) to give morpholine-4-carboxylic acid (4-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (60 mg, 32%) as a resin; 1H-NMR (300 MHz, d6-DMSO) 10.69 (1H, s), 9.21 (1H, s), 9.18 (1H, s), 8.60 (1H, s), 8.16-8.20 (2H, m), 8.10 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.82 (1H, d), 7.75 (1H, t), 7.57 (1H, t), 7.28 (1H, t), 6.98 (1H, d), 6.63 (1H, t), 6.58 (1H, d), 4.48 (2H, d), 3.55-3.59 (4H, m), 3.41-3.45 (4H, m); m/z (ES+) 483 [M+H]+, 242.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]=[C:2]1[N:6]([CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:23])[F:24])=[C:11]([F:28])[CH:10]=2)[S:3]1
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Reactant: ClCCN1CCCC1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=O)N(CCN4CCCC4)C3=O)cc2F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and 1-(2-Chloro-ethyl)-pyrrolidine as described in Example 1. 1H NMR (400 Hz, DMSO-d6) δ8.49 (s, 1H), 8.21 (dd, 1H), 8.05 (s, 1H), 7.87 (d, 1H), 7.64 (m, 2H), 7.31 (d, 1H), 3.86 (t, 2H), 2.76 (bs, 2H), 2.60 (bs, 4H), 1.73 (bs, 4H); LC/MS (m/z) [M+1]+ 506.2 (calculated for C24H20F4N3O3S, 506.49).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]([CH2:21][O:22][CH3:23])[CH2:19][CH3:20])[C:12]=1[N+:24]([O-])=O.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]([CH2:21][O:22][CH3:23])[CH2:19][CH3:20])[C:12]=1[NH2:24]
Reactant: CCC(COC)Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Product: CCC(COC)Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1N
Yield: 94.2 %

Procedure:
[4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (35 mg, 0.09 mmol) and SnCl2 (51 mg, 0.27 mmol) were treated substantially as described in Part D of Example 74a to yield 30 mg (94%) of 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 354.22 [(M+H)+, 100].
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([OH:16])[CH2:12]2)C1C=CC=CC=1.[ClH:23]>[Pd].C(O)C>[ClH:23].[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[C:11]1([OH:16])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: OC1(c2ncccn2)CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC1(c2ncccn2)CC2CCC(C1)N2

Procedure:
In an autoclave, 8-benzyl-3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-ol (5.0 g, 17 mmol), palladium on charcoal (3,5 g, 5% Pd/C, 50% water wet) ethanol (27.5 ml) and 2N HCl (2.5 ml) were mixed and hydrogenated under a pressure of 0.5 to 1.5 bar at 50° C. The reaction was followed by HPLC. After complete reaction (6 to 8 h) the mixture was filtered and the residue washed with ethanol. The filtrate was concentrated to dryness under vacuum at 50° and the crude product is purified by column chromatography (90 g silica gel, methanol:ammonia (25%) 50:1). Yield: 1.8 g (52%) as free base. Assay (HPLC): 99% area.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 46.5 %

Procedure:
9-Benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione 31-03 (900 mg, 46.51%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (30-03) (2 g, 3.824 mmol) as a white solid following the procedure as described for 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].C[Sn](C)(C)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>O1CCCC1.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>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: C[Sn](C)(C)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(-c2nccs2)cc(NC(C)=O)c1Cl
Yield: 29.6 %

Procedure:
A solution of methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (1.0 g, 4.05 mmol), 2-(trimethylstannyl)thiazole (2.9 g, 17.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.6 mmol) in tetrahydrofuran (75 mL) was heated under reflux for four hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was purified by column chromatography (50% ethyl acetate in hexane) to give methyl 4-acetamido-3-chloro-6-(2-thiazolyl)pyridine-2-carboxylate (0.38 g, 1.2 mmol), mp 187-8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: Oc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Product: Oc1ccc(Nc2ccccn2)cc1
Reaction time: 8 h

Procedure:
To a microwave reaction vessel was added 4-bromophenol (5.5773 mL, 59.317 mmol), 2-aminopyridine (5.5942 g, 59.317 mmol), Pd2(dba)3 (1.3658 g, 1.4829 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (2.5346 g, 5.9317 mmol), and sodium tert-butoxide (10.0798 g, 118.63 mmol). The vessel was capped and flushed with argon. Toluene was added and the vessel was flushed with argon. The temperature was brought to 100° C. to stir overnight. The reaction was monitored by LCMS to completion. The solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ SNAP cartridge (KP-Sil 340 g), eluting with a gradient of 1.5% to 6% methanol in DCM, to provide 4-(pyridin-2-ylamino)phenol. MS (ESI, pos. ion) m/z: 187.0 (M+1).