Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.Cl>CN(C)C(=O)C.O.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>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:28]2[CH:29]=[CH:24][CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1cccc(-c2ccc(O)cc2)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (1.00 g, 0.88 mmol) and potassium carbonate (4.80 g, 37.0 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.84 g, 17.5 mmol) and methyl (3-bromophenyl)acetate (4.00 g, 17.5 mmol) which was synthesized according to the method described in literature (Muller, R. N. et al., Eur. J. Org. Chem., 2002, vol. 23, pp. 3966-3973) in a mixture of N,N-dimethylacetamide-water (10:1, 66 ml), and the mixture was stirred at 110° C. for 6 hours. After the reaction mixture was poured into 0.2N hydrochloric acid and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give methyl (4′-hydroxy-1,1′-biphenyl-3-yl)acetate (2.83 g, yield: 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:14]=2[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(CS(N)(=O)=O)cc1
Yield: 100 %

Procedure:
4-Nitrophenylmethanesulfonamide (5.0 g, 23.1 mmol) was suspended in 90% of acetic acid and hydrogenated in the presence of palladium-carbon at ordinary temperature under normal pressure. The resulting reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to dryness to give 4.3 g of 4-aminophenylmethanesulfonamide. This product was added to a mixture comprising 40 ml of water and 4.1 ml of concentrated hydrochloric acid. The obtained mixture was stirred, followed by the dropwise addition of a saturated aqueous solution of 1.63 g (23.6 mmol) of sodium nitrite at 0° C. or below. The reaction mixture was added to an acetic acid solution saturated with sulfur dioxide (prepared by saturating 30 ml of acetic acid with sulfur dioxide and adding 0.97 g of cupric chloride dihydrate to the resulting solution) under cooling with ice and stirring. The resulting mixture was stirred at room temperature for 40 minutes and poured onto ice-water. The obtained mixture was saturated with common salt and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated to dryness to give 1.7 g of the title compound.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH2:29][NH:30][CH3:31])[N:22]2[CH3:28].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:30]([CH2:29][C:21]2[N:22]([CH3:28])[C:23]3[C:19]([CH:20]=2)=[C:18]([Cl:17])[CH:26]=[C:25]([Cl:27])[CH:24]=3)[CH3:31])=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cc2c(Cl)cc(Cl)cc2n1C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2c(Cl)cc(Cl)cc2n1C)C(=O)/C=C/c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
EDC (84.4 mg, 0.44 mmole) was added all at once to a solution of (E)-3-(6-amino-pyridin-3-yl)acrylic acid (65.7 mg, 0.40 mmole), 4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole (107.0 mg, 0.44 mmole), HOBt.H2O (59.5 mg, 0.44 mmole), and Et3N (0.14 mL, 1.0 mmole) in anhydrous DMF (4 mL) at RT. After 17 hr, the reaction was concentrated to dryness and the residue was re-concentrated from CHCl3/xylenes (2×). Flash chromatography on silica gel (7% MeOH in 1:1 EtOAc/CHCl3) gave the Rf 0.44 component (10% MeOH in 1:1 EtOAc/CHCl3) as a foam. This was solidified by re-concentration from MeOH/EtOAc/CHCl3 several times. This material was triturated with hot EtOAc/MeOH, and the mixture was cooled to 0° C. The title compound was collected by suction filtration. The filtrate was concentrated and the residue was triturated with EtOAc to afford additional title compound. The combined desired solids were dried in high vacuum at 50-60° C. to afford the title compound (108.9 mg, 70%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) 1.8:1 mixture of amide rotamers; δ 8.08-8.20 (2×s, 1H), 7.70-7.90 (2×d, 1H), 7.57-7.70 (2×s, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.18 (s, 1H), 6.97 (d, J=15.2 Hz, 1H), 6.45 and 6.15 (2×m, 4H), 5.02 and 4.82 (2×s, 2H), 3.60-3.80 (2×s, 3H), 2.99 and 3.11 (2×s, 3H); MS (ES) m/e 239 and 391 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)nc2c1ncn2Cc1ccccc1
Yield: 67.2 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and benzylamine (825 mg, 7.70 mmol) in 1-butanol (10 ml) were refluxed on heating for 8 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (171 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:25]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([NH2:25])=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1noc2c1-c1ccnc(N)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 80 °C
Yield: 24.3 %

Procedure:
To a solution of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine (0.025 g, 0.076 mmol) in 1,4-dioxane (1 mL) was added concentrated ammonium hydroxide (2.00 mL, 51.4 mmol) at room temperature. The reaction was heated to 80° C. for 17 h before silica gel was added. The solvent was removed under vacuum, the dry silica gel was packed and the adsorbed product was purified by flash chromatography (hexane/EtOAc 6:4 to 0:10) to give 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine as an off-white solid (0.006 g). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=5.26 Hz, 1H), 7.38 (td, J=2.20, 8.93 Hz, 2H), 7.34 (td, J=2.20, 8.47 Hz, 2H), 6.94 (d, J=5.26 Hz, 1H), 5.91 (s, 2H), 5.21 (d, J=12.82 Hz, 1H), 4.04 (d, J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 325 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (+/−)-ethyl 4-(1-{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}butyl)benzoate (26 mg, 0.064 mmol) was dissolved in methanol (0.13 ml) and tetrahydrofuran (0.070 ml) and treated with aqueous 2.0M lithium hydroxide (64 ul, 0.13 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo and the residue was acidified with aqueous 1.0M hydrochloric acid. The crude product was concentrated in vacuo a second time and was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH:21][CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[CH:18]=[CH:17][C:16]=2[F:28])([CH3:14])[N:13]=1)(C)(C)C.Cl.O1CCOCC1.C(O)(C(F)(F)F)=O>>[F:28][C:16]1[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][C:15]=1[C:12]1([CH3:14])[CH2:11][O:10][CH2:9][C:8]([NH2:7])=[N:13]1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NCc3ccco3)ccc2F)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cc(NCc3ccco3)ccc2F)COCC(N)=N1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A solution of (5-{2-fluoro-5-[(furan-2-ylmethyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (29 mg, 0.072 mmol) in 4M HCl/dioxane (0.719 ml, 2.88 mmol) was stirred at rt for 2 h, then heated at 50° C. for 2 h. TFA (0.005 ml, 0.072 mmol) was added and stirring at 50° C. was continued for 7 h. The reaction mixture was quenched with water and diluted with EtOAc. The phases were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to leave the crude title compound that was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 90% ACN+0.1% TFA) and obtained as a free base after filtration over an SCX cartridge.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH:21][C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)=[O:13]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using preparation method 1, 4-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 3,4-dichlorobenzylamine (123 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (210 mg, 94%). NMR 1H (ppm, CDCl3): 7.87-7.82 (m, 2H), 7.67-7.56 (m, 4H), 7.48-7.36 (m, 5H), 7.19 (tt, J3=7.8 Hz, J4=2.1 Hz, 1H), 6.51 (br. s, 1H), 4.61 (m, 2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]1[O:41][C:40]2[C:33](=[CH:34][C:35]([N+:42]([O-:44])=[O:43])=[C:36]([CH:39]=2)[CH:37]=O)[O:32]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:37][C:36]2[CH:39]=[C:40]3[O:41][CH2:31][O:32][C:33]3=[CH:34][C:35]=2[N+:42]([O-:44])=[O:43])[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4,5-methylenedioxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]1([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]1([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)C1(N)CCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC2(C(=O)N(C)C)CCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.81 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 76-3 (2.89 mmol, crude form) as starting materials, 0.27 g of the title compound (pale yellow solid) was obtained by a similar method to Step 4-2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]=[N+:10]=[N-:11])=[O:8])([O-:3])=[O:2].[C:15](#[N:17])[CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]1[CH:4]=[C:5]([C:6]23[CH2:7][N:17]([CH2:13][CH2:12]2)[CH2:15][CH2:16]3)[N:11]=[N:10]1)=[O:8])([O-:3])=[O:2]
Reactant: CC#N
Reactant: [N-]=[N+]=NC(=O)c1cccc([N+](=O)[O-])c1
Product: O=C(c1cccc([N+](=O)[O-])c1)n1cc(C23CCN(CC2)C3)nn1
Reaction time: 8 h

Procedure:
A solution of 4-(triphenylphosphinemethylenecarbonyl)-1-azabicyclo [2.2.1]heptane (D24) (4 g, 0.01 mole) in dry acetonitrile (80 ml) was treated with m-nitrobenzoylazide* (3.8 g, 0.020 mole) under nitrogen and the solution heated to reflux for 2 h. The solution was then concentrated in vacuo to a gum which was dissolved in ethyl acetate (30 ml) and allowed to stand at 0° C. overnight when the title compound (D25) (1.35 g, 0.0043 mole, 43%) crystallised out.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1>COCCOC>[CH3:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:9])[C:6](=[O:8])[N:7]=1
Reactant: Cc1nc(O)c(C)c(Cl)n1
Reactant: Cn1cccc1CCN
Solvent: COCCOC
Product: Cc1nc(=O)c(C)c(NCCc2cccn2C)[nH]1
Temperature: 90 °C
Yield: 82.9 %

Procedure:
A stirred suspension of 2.00 g (12.9 mmol) of 2,5-dimethyl-4-hydroxy-6-chloropyrimidine and 6.5 mL (52 mmol, 4 equiv.) of 2-(2-aminoethyl)-1-methylpyrrole in 10 mL of DME was heated at 90° C. for 18 hours under a dry atmosphere. The reaction mixture was cooled to 23° C. and filtered. The isolated solids were rinsed with Et2O, H2O, and MeOH and then recrystallized from MeOH to afford 2.63 g 83% (10.7 mmol) of pure product, m.p. 246°-247° C. as a white powder.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:21](=[O:26])[CH:22]=[C:23]([CH3:24])[N:25]=[C:28]4[CH3:29])=[CH:16][C:15]=3[F:27])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C/C(N)=C/C(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cc(=O)n(-c2ccc(NCCC34CC5CC(CC(C5)C3)C4)c(F)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 3 %

Procedure:
A mixture of (Z)—N-(4-((2-(adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-aminobut-2-enamide (0.31 g, 0.83 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a red brown solid (10 mg, 3%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([C:24]#[N:25])[CH:19]=[C:20]([CH:23]=2)[C:21]#[N:22])=[O:15])=[N:6][C:7]([O:12]C)=[N:8][C:9]=1[O:10]C)([CH3:3])[CH3:2]>C(Br)(=O)C>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:12])[NH:6][C:5]=1[C:14]([C:16]1[CH:17]=[C:18]([C:24]#[N:25])[CH:19]=[C:20]([CH:23]=1)[C:21]#[N:22])=[O:15])([CH3:3])[CH3:2]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C#N)cc(C#N)c2)n1
Agent: CC(=O)Br
Product: CC(C)c1c(C(=O)c2cc(C#N)cc(C#N)c2)[nH]c(=O)[nH]c1=O

Procedure:
A solution of 5-(5-isopropyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-isophthalonitrile (0.018 g, 0.0535 mmol) in acetyl bromide (0.7 mL) was heated at 60° C. for 5 h. Reaction mixture was concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/dichloromethane) to give a yellow film (0.017 g, 97%). 1H NMR (300 MHz, CD3OD): δ 8.65 (s, 2H), 8.52 (s, 1H), 2.5-2.3 (m, 1H), 1.14 (s, 3H), 1.10 (s, 3H). Mass spectrum: 307.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[N:8]2)[CH2:3]1>CCO.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH2:3]1
Reactant: CN1CCC(n2cc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(n2cc(N)cn2)C1

Procedure:
A solution of 1-(1-methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole A23 (0.575 g, 2.93 mmol) and 10% Pd/C (0.061 g) in EtOH (15 mL) was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound A24 as a red oil (0.555 g, quantitative). 1H NMR (300 MHz, MeOD) δ 2.27-2.42 (m, 1H), 2.72-2.76 (m, 2H), 3.02-3.10 (m, 1H), 3.46-3.55 (m, 1H), 3.70-3.85 (m, 4H), 5.14-5.26 (m, 1H), 7.33 (s, 1H), 7.46 (m, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.C1COCC1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[F:26][C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[CH:31][C:32]=1Br>CCCCCC>[F:26][C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[CH:31][C:32]=1[B:13]([OH:18])[OH:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c(F)c1
Temperature: -40 °C

Procedure:
To a mixture of toluene (160 ml) and THF (40 ml) are added triisopropyl borate (13.56 ml, 58.42 mmole) and 3-fluoro-4-bromotoluene (10.0 g, 48.69 mmole). The mixture is cooled down to −40° C. and n-Butylithium (2.5M in hexane) (23.4 ml, 58.42 mmole) is added slowly over 1 h and the mixture is stirred for an additional hour while the temperature is held at −40° C. The acetone/dry ice bath is removed and the reaction mixture is allowed to warm to −20° C. before a 2.5M HCl solution (20 ml) is added. When the mixture reached rt, the aqueous layer is extracted with EtOAc (3×50 ml), organic extracts are combined, dried over MgSO4 (anhydrous) and evaporated under reduced pressure to give a yellow solid, which is recrystallised from acetonitrile, affording the title product.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:12](=[O:13])[C:11]([Cl:14])=[C:10]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:9]([S:27][CH2:28][CH2:29][CH3:30])=[N:8]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>CN(C)C=O>[Cl:14][C:11]1[C:12](=[O:13])[NH:7][N:8]=[C:9]([S:27][CH2:28][CH2:29][CH3:30])[C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: CCCSc1nn(COCC[Si](C)(C)C)c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: CCCSc1n[nH]c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture comprising 256 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-n-propylmercapto-3(2H)pyridazinone prepared in Reference Example 5, 3 ml of tetra-n-butylammonium fluoride (1M tetrahydrofuran solution) and 1.5 ml of N,N-dimethylformamide, was stirred at a temperature of 150° C. for 3 hours. A 1N hydrochloric acid aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water and a sodium hydrogencarbonate aqueous solution in this order, and dried over sodium sulfate. The solvent was distilled off and the residue thereby obtained was purified by silica gel thin layer chromatography by using benzene-ethyl acetate (1:1 v/v) as the developer, to obtain 39 mg of the above identified compound as a light yellow solid substance. The product was changed into slightly yellow crystals having a melting point of from 129° to 130° C. by the recrystallization thereof from a solvent mixture of ethyl acetate-diethyl ether-n-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]3)[C:6]=12.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (750 mg, 1.84 mmol) in CH2Cl2 (2 mL) was added a prepared solution of 1:1 trifluoroacetic acid (2.0 mL, 26 mmol) in CH2Cl2 (2 mL). After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate solution (75 mL) was slowly added. The mixture was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine] (555 mg, 98%) as a yellow-brown solid. ESI-MS m/z calc. 307.1, found 307.9 (M+1)+; Retention time: 1.12 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 9.38 (s, 1H), 6.49 (s, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.36 (d, J=11.6 Hz, 2H), 3.26 (d, J=6.1 Hz, 4H), 2.78 (s, 2H), 2.40 (s, 3H), 2.11 (d, J=14.4 Hz, 2H), 1.69 (s, 2H).