Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][C@@H:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][C@@H:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)N[C@@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 51 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.162 mmol) and (2S)-2-amino-1-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1S)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (33 mg, 51% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.27 (d, J=7.6 Hz, 1 H), 8.50 (s, 1 H), 7.33 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.98 (m, 2 H), 4.27 (m, 6 H), 3.78 (dd, J=11.2, 3.6 Hz, 1 H), 3.65 (dd, J=11.2, 6 Hz, 1 H), 1.29 (d, J=6.8 Hz, 3 H), 1.19 (m, 3 H); MS m/z 400 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](C(=O)C(C)(C)C)[N:20]=[CH:19]4)[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3N(Cc3ccccc3)C4)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of 1-(5-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-ylamino)-1H-indazol-1-yl)-2,2-dimethylpropan-1-one (the intermediate benzyl compound of Example 11, 175 mg, 0.44 mmol) in methanol (2.5 mL) was treated with potassium carbonate (72 mg, 0.52 mmol), and the mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, and the organic phase was dried over sodium sulfate and evaporated to a residue. Chromatography of the residue on silica gel afforded the title compound (70 mg, 50%). 1H NMR (CDCl3) δ 9.80 (br s, 1H), 7.88 (s, 1H), 7.39-7.21 (m, 6H), 6.92-6.85 (m, 2H), 3.80 (m, 1H), 3.63 (s, 1H), 3.16-3.12 (m, 2H), 2.40-2.37 (m, 1H), 2.04-1.96 (m, 2H), 1.85-1.76 (m, 2H), 1.60-1.40 (m, 2H)
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:41])([F:40])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32]C(=O)OC(C)(C)C)=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[F:41][C:9]([F:8])([F:40])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH2:23][CH2:24]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
TFA (0.5 mL, 0.15 mmol) was added to tert-butyl N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]carbamate (obtained as described in Example 146, 72 mg, 0.15 mmol) in DCM (2 mL). The resulting solution was stirred at ambient temperature for 2 hours and then evaporated to dryness. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated and further purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford 4-[[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline (32 mg, 56%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH:1]1([CH2:4][CH2:5][N:6]([CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
To a solution of N-(2-cyclopropylethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (100 mg, 0.33 mmol) in anhydrous MeCN (7 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (94 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.5 μl, 0.33 mmol). The resultant solution was heated to reflux and stirred for 2.5 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:200–1:100 EtOAc:cyclohexane afforded the title compound as a colourless oil (141 mg).
Reaction SMILES: [CH:1]1([Sn:7](C2CCCCC2)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Sn](Cl)(Cl)(Cl)[Cl:34].O>CCCCCC>[CH:1]1([Sn:7]([Cl:34])([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC([Sn](C2CCCCC2)(C2CCCCC2)C2CCCCC2)CC1
Reactant: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cl[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
55.1 g of tetracyclohexyltin (122 mmol) and 50 ml of toluene were mixed together in a 200 ml eggplant type flask, and containing a stirrer. Then, 18.1 ml of tin tetrachloride (155 mmol) was added, and the mixture was refluxed for 3 hours. Upon completion of the reaction, the mixture was cooled to 0° C., and 30 ml of water and 50 ml of hexane were added. After the hexane layer was separated, the solid precipitate, which had been precipitated by removing the solvent under reduced pressure, was washed with 20 ml of acetonitrile, and dried under a vacuum, to yield 39.1 g of the final product (yield=59.5%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:9]=1)[C:15]([OH:17])=[O:16])([OH:3])=[O:19]
Reactant: COC(=O)c1cc(C[C@H](N)C(=O)OC)ccc1O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: Cl
Product: O=C(NC(Cc1ccc(O)c(C(=O)O)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the tile compound of example 121.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13](I)=[C:12]([F:18])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)#[CH:20]>C(N(CC)CC)C.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.[Cu]I>[CH2:27]([C@H:24]1[CH2:23][CH2:22][C@H:21]([C:19]#[C:20][C:13]2[C:14]([F:16])=[CH:15][C:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)=[CH:11][C:12]=2[F:18])[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCC[C@H]1CC[C@H](c2cc(F)c(I)c(F)c2)CC1
Reactant: C#C[C@H]1CC[C@H](CCC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC[C@H]1CC[C@H](C#Cc2c(F)cc([C@H]3CC[C@H](CCC)CC3)cc2F)CC1
Temperature: 105 °C
Reaction time: 17 h

Procedure:
A mixture of 0.8 g of 1-(trans-4-propylcyclohexyl)-3,5-difluoro-4-iodobenzene, 0.379 g of trans-1-ethynyl-4-propylcyclohexane, 0.023 g of tetrakis(triphenylphosphine)palladium(0) and 0.009 g of copper(I) iodide in 20 ml of triethylamine is stirred at 105° C. for 17 hrs. Thereafter, the mixture is cooled, partitioned between ether and water, the combined organic phases are dried over magnesium sulphate, filtered and the filtrate is evaporated on a rotary evaporator. Chromatography on 140 g of silica gel with hexane and three-fold crystallization from methanol, hexane and again methanol gives 0.376 g of 1-(trans-4-propylcyclohexylethynyl)-2,6-difluoro-4-(trans-4-propylcyclohexyl)benzene, m.p. (C/N) 120.2° C., cl.p. (N/I) 171.4° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH:26]=[CH:25][N:24]=[CH:23]5)[CH:17]=4)=[N:13][C:14](N)=[C:9]3[C:8]([CH2:27][CH3:28])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N([O-])=[O:30].[Na+].[NH4+].[OH-]>O.OS(O)(=O)=O.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH:26]=[CH:25][N:24]=[CH:23]5)[CH:17]=4)=[N:13][C:14](=[O:30])[C:9]3=[C:8]([CH2:27][CH3:28])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2nc(-c3cccc(-n4ccnc4)c3)nc(N)c12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(-n4ccnc4)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-cyclopentyl-3-ethyl-6-[3-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine (6.24 g, 16.7 mmol), in 45 ml of H2O/H2SO4 (1:1) in an EtOH/ice bath was added sodium nitrite (5.77 g) in water (5 ml) in small portions over 1.5 hours. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water (500 ml) and neutralized with NH4OH to afford a yellow precipitate which was collected by filtration, washed with water, then ether. The product was recrystallized from EtOAc/MeOH, then MeOH to afford 1-cyclopentyl-3-ethyl-6-[3-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 264-265° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:25])=[CH:4][N:3]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:25][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)N3CCCC3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N5CCCC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (0.045 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 90% ethyl acetate in dichloromethane and then 2.5% to 7% methanol in ethyl acetate. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.007 g, 12%); 1H-NMR (500 MHz, DMSO-d6) 1.78 (m, 2H) and 1.90 (m, 2H) (pyrrolidine 3-CH2 and 4-CH2), 2.65 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.18 (s, 2H, NCH2CO), 3.32 (t, J=7.29 Hz, 2H) and 3.53 (t, J=6.48 Hz, 2H) (pyrrolidine 2-CH2 and 5-CH2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.58 Hz, 2H) and 8.01 (d, J=9.58 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.14 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH2:36])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:39]([CH2:41][CH2:42][C:43](Cl)=[S:44])#[N:40].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH:36][C:43](=[S:44])[CH2:42][CH2:41][C:39]#[N:40])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCC(=S)Cl
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 3.5 h

Procedure:
7-Amino-3-cephem-3ol-4-carboxylic acid benzhydryl ester p-toluenesulfonate salt [Helv. Chim. Acta 57, 1919 (1974)], (242 mg.) is dissolved in methylene chloride (5 ml.), cooled in an ice bath, and cyanomethylthioacetyl chloride (68 mg.) in methylene chloride (3 ml.) is added, followed by 125 μl of triethylamine. The mixture is stirred for 3.5 hours at 0°-5° and then is allowed to stand overnight in the refrigerator. After diluting with methylene chloride, the reaction mixture is washed with water, then with pH 4 buffer, and dried (Na2SO4). Solvent is removed in vacuo yielding the desired product as a oil (204 mg.); NMR (CDCl3, δ) 3.33 (m,CH2), 3.45 (s, NCCH2SCH2 --) 5.05 (d, J=4.5 Hz, H6), 5.65 (q. J=4.5, 9Hz, H7), 6.93 (s,CHφ2), 7.33 (s, aromatic H's), 7.80 (d, J=9Hz, NH); νmax (CH2Cl2) 3380, 3310, 2225, 1785, 1735, 1690 cm-1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:4][CH2:3]1.ClC(OCC)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].Cl>O1CCCC1.C(N(CC)CC)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]=[C:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)[CH3:22]
Reactant: CCNCC
Reactant: O=C(O)CCCC=C1CCC(=O)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCCC=C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 21 ml of anhydrous tetrahydrofuran were dissolved 1.50 g of 5-(4-oxocyclohexylidene)-valeric acid and 1.17 ml of triethylamine. Then, 4.50 ml of a solution of 0.80 ml of ethyl chloroformate in anhydrous tetrahydrofuran was dropwise added at −20° C., and the resulting mixture was stirred at the same temperature as above for one hour. Then, 4.50 ml of a solution of anhydrous tetrahydrofuran containing 2.00 ml of diethylamine was dropwise added at the same temperature, and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturate aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:1] gave 1.30 g of N,N-diethyl-5-(4-oxocyclohexylidene)-valeramide as a colorless oily product.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)=[O:9]>>[C:1]([O:4][CH2:7][C:8](=[O:9])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
1.26 g of sodium acetate are added to a solution of 1.35 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone in 25 ml of alcohol and heated to boiling under reflux. After 6 hours, the reaction mixture is filtered from separated sodium bromide and evaporated. The residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated at 50°. There is obtained (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate of m.p. 166°-168° (from ethyl acetate/ether).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[CH:10][N:9]=[N:8][CH:7]=1)=[O:5])C>C1COCC1>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:13](=[O:24])[NH:12][C:11]2=[CH:10][N:9]=[N:8][CH:7]=[C:6]2[C:4]1=[O:5]
Reactant: CCOC(=O)c1cnncc1NC(=O)Cc1c(F)cc(F)cc1F
Solvent: C1CCOC1
Product: O=C1Nc2cnncc2C(=O)C1c1c(F)cc(F)cc1F
Temperature: 0 °C

Procedure:
The product from Step 1 (2.5 g) was dissolved in dry THF (50 ml) and the flask purged with nitrogen. Sodium bis-trimethylsilylamide (22.1 ml of a 1M solution in THF) was added dropwise with stirring at 0° C. A yellow precipitate appeared, and the reaction was stirred for 3 hours at 0° C. The reaction was quenched with concentrated hydrochloric acid (5 ml) at 0° C. and then poured onto ice water, extracted with DCM and dried over magnesium sulphate. The solvent was evaporated to give 3-(2,4,6-trifluorophenyl)-1H-pyrido[2,3-d]pyridazine-2,4-dione as a yellow solid. Further product crystallised out of the aqueous solution overnight, to give a total yield of 1.29 g, m.p. >300° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18][OH:19])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.[OH-].[Na+]>CN(C)C=O>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:20])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18][OH:19])[S:14][C:9]1=2)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2sc(C=NO)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C=NO)sc21
Reaction time: 1 h
Yield: 80 %

Procedure:
For 1 hour, 1 g of 4,7-dihydro-7-ethyl-2-hydroxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was refluxed in 30 ml of 10%-sodium hydroxide. After cooling, the solution was filtered and acidified with 10%-hydrochloric acid. After filtration 4,7-dihydro-7-ethyl-2-hydroxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid was obtained in a yield of 80%. M.P.: 315°-317° C. (N,N-dimethylformamide).
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]([CH2:17][CH2:18]Br)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([F:16])[CH:10]=1)=[O:6]>O1CCCC1>[Br:3][CH:4]1[CH2:17][CH2:18][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([F:16])[CH:10]=2)[C:5]1=[O:6]
Reactant: Cc1ccc(CNC(=O)C(Br)CCBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of NaH (0.76 g, 19 mmol) in tetrahydrofuran (50 mL) was added dropwise over ˜½ hour a solution of 2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide (4.5 g, 12.2 mmol) in tetrahydrofuran (30 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered and the solvent evaporated.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.Cl[C:44](Cl)([O:46][C:47](=O)[O:48]C(Cl)(Cl)Cl)Cl.O1CCCC1>N1C=CC=CC=1.Cl.CO>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][C:47]([O:46][CH3:44])=[O:48])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)NCCN1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
(±)-cis-N1-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (144 mg) was dissolved in pyridine (3 ml), triethylamine (138 μl) was added, and the mixture was stirred at room temperature for 5 minutes. A solution prepared by adding triphosgene (49 mg) to tetrahydrofuran (1 ml) containing methanol (20 μl) was added dropwise to this solution. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was dissolved in a 9:1 mixed solvent of dichloromethane and methanol. Water was added to the solution to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a colorless foamy substance. This product was suspended in 1N hydrochloric acid (0.2 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (60 mg) as a pale yellow foamy substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][C:14]=3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]=3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Yield: 93.9 %

Procedure:
The title compound was prepared using the general procedure set forth in Example 3.A. using N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (0.453 g, 1.09 mmol), ammonium formate (0.69 g, 10.87 mmol), palladium, 10% wt. on activated carbon (100 mg) and MeOH (15 mL). 0.334 g (94%) Of the title compound was obtained as a white foam.