Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[SH:25][C:26]1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:25][C:26]2[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Cc1ccc(S)nn1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(C)nn2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 3-mercapto-6-methylpyridazine. Light yellow liquid (43%). MS (EI): 400.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:40]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:40][O:38][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:16]3=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a stirred solution of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.4 g, 14.8 mmol), chloroiodomethane (2.7 mL, 37.0 mmol) in anhydrous tetrahydrofuran (200 mL) was added cesium carbonate (15.4 g, 47.4 mmol) under argon. The mixture was stirred at ambient temperature for 16 h, then filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/hexanes, 1/5) followed by the treatment with diethyl ether/hexanes to afford 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (4.1 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 15H), 7.16-7.09 (m, 1H), 7.07-6.90 (m, 3H), 6.62-6.38 (m, 4H), 5.03-4.90 (m, 3H), 4.73 (d, J=9.0 Hz, 1H); MS (ES+) m/z 510.1 (M+1).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.6 %

Procedure:
Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 6-aminonicotinonitrile (104 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature. The temperature was increased to 60° C. and stirred for 4 hours, then heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer was evaporated in vacuo. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were neutralised with MP-carbonate and evaporated to dryness to afford the product (100 mg, 17.6%). m/z (ES+) (M+H)+=719.51; HPLC tR=3.58 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[N:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][N:16]=1>CN(C=O)C.O>[CH2:21]([C:18]1[CH:17]=[N:16][C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:20][CH:19]=1)[CH2:22][CH3:23]
Reactant: CCCc1cnc(Cl)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a stirring solution of piperidin-4-ol (2.33 g, 23.0 mmol, Aldrich) and potassium carbonate (6.36 g, 46.0 mmol, EMD) in DMF (15 mL) at room temperature was added 2-chloro-5-propylpyrimidine (4.33 g, 27.6 mmol, Wako). The reaction mixture was heated at 100° C. for 3 h then diluted with H2O. The resulting mixture was extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 5.01 g of desired product as a white solid. MS (ESI) 222 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[OH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:8]=1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: OCCCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(OCCCc2ccccn2)n1
Yield: 23.8 %

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (150 mg.) was added to a stirred mixture of 2-(3-hydroxypropyl)pyridine (82 mg.), a 50% w/w dispersion of sodium hydride in oil (30 mg.) and DMF (2 ml.) and the mixture heated at 90° for 1 hour. The mixture was evaporated to dryness and the residue partitioned between water and EtOAc. The EtOAc phase was dried and evaporated to dryness. The residue was subjected to preparative thin layer chromatography using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:0.5 v/v/v as developing solvent. The band having Rf 0.6 was eluted with MeOH and the MeOH evaporated to dryness to give 2-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]-pyrimid-2-yloxy)propyl]pyridine (45 mg.), which was characterised as the bis hydrogen maleate salt, m.p. 118°-120° (after crystallisation from acetone/ether).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]=2[NH2:25])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[C:10]=2[NH:25][C:28](=[O:32])[C:29]([NH:25][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:30])=[CH:7][CH:8]=1
Reactant: Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1)C(=O)Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4,4″-Bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-ylamine (700 mg, 1.84 mmol) in pyridine (5 mL) was treated with oxalyl chloride (73 μL, 0.837 mmol). The resulting suspension was stirred at rt overnight under Ar, then poured into H2O. The precipitate was filtered, washed with H2O and dried in vacuo. The resulting solid was crystallized from toluene/heptane, then recrystallized from toluene to afford N,N′-Bis-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yl)-oxalamide (430 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12]>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([CH3:12])[N:6]2[N:5]=[C:4]([OH:7])[N:3]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1n[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(O)nc2n1
Yield: 88.2 %

Procedure:
To a solution of 5-amino-2,4-dihydro-3H-1,2,4-triazol-3-one (29 g, 0.29 mol) in glacial acetic acid (140 mL) was added pentane2,4-dione (29 g, 0.29 mol) and the solution was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. The solid was filtered and washed with ethanol (200 mL) to give the product (42 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)=[O:9].C(O)(=O)C.OO.O>C(OO)(=O)C>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=23)=[CH:15][CH:14]=1)[CH3:17]
Reactant: CCc1ccc(C(=O)c2ccccc2N)cc1
Agent: CC(=O)OO
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(-c2onc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55 %

Procedure:
(2-Aminophenyl) (4-ethylphenyl)methanone, 60 g, (0.27 mole) was dissolved in 700 ml of 3% peracetic acid (prepared by warming a mixture of 500 ml of glacial acetic acid and 200 ml of 30% hydrogen peroxide on a steam bath for 1/2 hr, followed by cooling to 25° C.). The solution was allowed to stand for 60 hr, then poured into two liters of water. The mixture was extracted with methylene chloride and the organic extracts were diluted with ethyl acetate and extracted with dilute sodium hydroxide. The organic phase was then concentrated and the residue was chromatographed on silica gel, eluting with benzene. The product-containing benzene fractions were concentrated and the residue was distilled. The fraction boiling at 131° C./0.02 mmHg was collected and recrystallized from isopropanol to give 33.2 g (55%) of pale yellow crystals, m.p. 42.0°-42.5° C.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][O:8][CH:9]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][C:14]2[O:13][C:12]([CH3:23])=[N:11][C:10]1=2)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:23][C:12]1[O:13][C:14]2[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:9]([O:8][CH2:7][CH2:6][OH:5])[C:10]=2[N:11]=1
Reactant: Cc1nc2c(o1)CCc1ccccc1C2OCC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1nc2c(o1)CCc1ccccc1C2OCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
To a solution of (2-methyl-9,10-dihydro-4H-1-oxa-3-aza-benzo[f]azulen-4-yloxy)-acetic acid tert-butyl ester (1.4 g, 4.3 mmol) in dry ether (10 mL) was added a suspension of lithium aluminum hydride (245 mg, 6.5 mmol) in dry ether (40 mL). Stirring at room temperature for 1.5 h. The reaction was quenched with water an the product extracted with ether. The combined ether phases were dried MgSO4, filtered and concentrated in vacuo to give 900 mg (91%) of 2-(2-methyl-9,10-dihydro-4H-1-oxa-3-aza-benzo[f]azulen-4-yloxy)-ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCNCC2)cc1
Yield: 100.6 %

Procedure:
41.7 g of benzyl 4-[4-(tert-butyloxycarbonylaminomethyl)benzylaminocarbonyl]piperazine-1-carboxylate (starting material A5) in 1.0 l of methanol are hydrogenated over palladium/carbon (5%) for 4 h. The catalyst is filtered off and the solvent is removed, giving 30.3 g of the title compound as a colorless oil.
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)=[CH:25][CH:26]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncccc2n1Cc1ccccc1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2-c2ccc(Cl)cc2)c2cccnc2c1=O
Reaction time: 15 h
Yield: 69.2 %

Procedure:
To a brown solution of ethyl 1-((4′-chlorobiphenyl-2-yl)methyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (28) (257 mg, 0.61 mmol) in methanol (15 mL) was added the solid lithium hydroxide monohydrate (515 mg, 12.3 mmol) at room temperature under a nitrogen atmosphere. It gave a clear solution within 30 minutes and the resulting dark brown solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the mixture was diluted with water and the methanol was removed under vacuum. The basic aqueous layer was diluted with water and the brown solids were filtered off using filter paper. Then, the filtrate was neutralized with 1.0N HCl. The precipitated off-white solids were collected by filtration and washed with water and hexanes. After drying in air, 165 mg of 1-((4′-chlorobiphenyl-2-yl)methyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (29) (68.8% yield) was isolated as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCN2CCOCC2)cc1
Temperature: 90 °C

Procedure:
To a solution of 0.1 g (0.48 mmol, 1.0 eq.) of tert-butyl 4-hydroxyphenylcarbamate in 5 mL of p-dioxane was added 0.13 g (0.72 mmol, 1.5 eq.) of 4-(2-chloroethyl)morpholine and 0.47 g (1.43 mmol, 3.0 eq.) cesium carbonate. The suspension was heated at 90° C. for 16 h. The reaction mixture was allowed to cool to room temperature and filtered. The solvent was removed in vacuo to provide tert-butyl 4-(2-morpholinoethoxy)phenylcarbamate (I-19), which was redissolved in 30% v/v TFA/methylene chloride and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the residue was redissolved in methylene chloride. The organic solution was washed with sat. NaHCO3, dried (Na2SO4) and the solvent was removed in vacuo to provide 95 mg (0.43 mmol, 95%) of (4-(2-morpholinoethoxy)-benzenamine (I-20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C([O+](CC)CC)C.[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:36]([NH:38][NH2:39])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:36]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][N:30]=3)=[N:38][N:39]=[C:13]2[CH2:12]1)=[O:10]
Reactant: NNC(=O)c1cnccn1
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a suspension of 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (I3)(0.78 g, 3.04 mmol) in Dichloromethane (DCM) (7.60 ml) was added triethyloxonium tetrafluoroborate (0.606 g, 3.19 mmol) and the mixture was stirred at room temperature under argon. After 5-10 minutes it turned to a yellow solution. TLC showed the formation of the imidate (some unreacted starting material always present due to instability of imidate on TLC). After 1 hour 2-pyrazinecarbohydrazide (0.504 g, 3.65 mmol, commercially available) was added but it was insoluble. After 15 minutes the solvent was evaporated in vacuo and the residue taken in n-butanol (7.60 ml) and heated at reflux (120° C.). After 2 hours LCMS showed a main peak which is consistent with the desired product. It was concentrated in vacuo and the residue was purified by flash chromatography (Biotage SP4, 40+M cartridge) with a gradient of 2M ammonia in MeOH 0 to 10% in DCM. The crude product was then dissolved in EtOAc (50 mL), the precipitate filtered off (50 mg of impurity by LCMS) and the solution washed with sat. NH4Cl (30 mL), water (30 mL) and brine (30 mL) and finally dried over MgSO4 to afford an off-white solid that was fruther purified by MDAP to isolate the desired product in 310 mg as a white solid.
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([Cl:16])([F:15])[C:11]([F:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>CO>[Cl:16][C:10]([C:9]1[NH:22][C:20](=[O:21])[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=1)([F:15])[C:11]([F:12])([F:13])[F:14]
Reactant: NC(=O)CC(N)=O
Reactant: CCCCOC=CC(=O)C(F)(Cl)C(F)(F)F
Agent: [Na]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(Cl)C(F)(F)F)[nH]c1=O

Procedure:
0.33 g (14.4 mmol) of sodium were dissolved in 50 ml of methanol, 3.16 g (12.03 mmol) of 1-butoxy-4-chloro-4,5,5,5-tetrafluoropent-1-en-3-one and 1.27 g (12.03 mmol) of malonamide were added and the mixture was heated under reflux for 7 h. The mixture was concentrated, and 1N hydrochloric acid was then added. The resulting precipitate was filtered off with suction and dried. This gave 380 mg (12% of theory) of a yellowish powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:16]I>C1OCCOCCOCCOCCOC1.CN(C)C=O>[CH3:1][O:2][C:3]([CH3:16])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(OC)C(=O)OCC
Reactant: CI
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OC)C(=O)OCC
Yield: 50 %

Procedure:
Diethyl methoxymalonate (31.0 grams, 0.2 mole), prepared in Example LIII Part A, sodium hydride (3.91 grams of 60% reagent, 0.2 mole), methyl iodide (46.27 grams, 0.3 mole) and 15-crown-5 (2 drops) were reacted in 300 millilaters of N,N-dimethylformamide in a manner similar to that described in Example LII Part A to give 23.77 grams (0.1 mole) of diethyl methoxy(methyl)malonate. NMR analysis of the product indicated the following:
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49][OH:50].NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:53]=[CH:52][CH:51]=[C:48]([CH2:49][OH:50])[CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1cccc(CO)c1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5cccc(CO)c5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-aminobenzylalcohol as the aniline component. (12%, MS=613.3 (M+H))
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:13][CH3:14])[CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1.[C:15]([NH:20][NH2:21])([O:17][CH2:18][CH3:19])=[O:16].C(O)CCCC>>[C:15]([NH:20][NH:21][C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:13][CH3:14])[CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCN(CC(C)O)c1ccc(Cl)nn1
Reactant: CCOC(=O)NN
Solvent: CCCCCO
Product: CCOC(=O)NNc1ccc(N(CC)CC(C)O)nn1
Reaction time: 4 h

Procedure:
A mixture of 11 g 3-chloro-6-[N-(2-hydroxypropyl)ethylamino]pyridazine which can be be prepared as described in Example 4 of U.S. Pat. No. 3,769,278 and 11 g monocarbethoxyhydrazine in 55 ml n. pentylalcohol is warmed up to 140° C and kept at this temperature for 4 hours. After cooling the solution is extracted several times with water and then extracts collected together are extracted with ethyl ether. The aqueous phase is treated at room temperature with sodium bicarbonate until complete precipitation. The precipitate is collected, washed with water and dried under vacuum at room temperature on phosphorus pentaoxide to give with good yield 3-(2-carbethoxyhydrazino)-6-[N-(2-hydroxypropyl)ethylamino]-pyridazine melting at 160° -162° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][N:25]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3n[nH]c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=476.1.