Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19](C2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[NH2:22][C:21]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=3)[N:7]=2)[CH:18]=[N:17][C:16]=1[Cl:15]
Reactant: CC1(C)OC(c2cnc(Cl)c(N)c2)OC1(C)C
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(N)c3)ccc2n1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.05 g, 0.2 mmol, Aurigene, Bangalore, India), 2-chloro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridin-3-amine from Step 1 (0.07 g, 0.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.01 g, 0.02 mmol), sodium carbonate (0.05 g, 0.5 mmol), and dioxane-H2O (4:1, 2 mL). Ar was bubbled in for 1 minute. The reaction mixture was sealed and heated at 100° C. for 2 h before cooled down to room temperature. The mixture was filtered through a Celite® (diatomaceous earth) pad, the filtercake was washed with MeOH-DCM (50%), and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (10 to 50% MeOH/CH2Cl2) provided N-(6-(5-amino-6-chloropyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (0.03 g, 42% yield) as a white solid. MS (ESI positive ion) m/z: 303 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.11 (s, 3H), 5.84 (s, 2H), 7.72 (d, J=9.39 Hz, 1H), 7.77 (d, J=2.15 Hz, 1H), 8.08 (d, J=9.39 Hz, 1H), 8.23 (d, J=2.15 Hz, 1H), 8.28 (s, 1H), 10.93 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:52]=[CH:51][C:12]([CH2:13][CH:14]([C:41]([O:43]CC2C=CC=CC=2)=[O:42])[C:15]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:29][CH2:28]2)([OH:26])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].[C]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([C:41]([OH:43])=[O:42])[C:15]([C@H:27]2[CH2:28][CH2:29][C@@H:30]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:31][CH2:32]2)([OH:26])[C:16]([OH:18])=[O:17])=[CH:51][CH:52]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of dibenzyl 3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-2-(cis-4-((tert-butyldimethylsilyl)oxy)-cyclohexyl)-2-hydroxysuccinate (120 mg, 0.16 mmol) was added 10% Pd-carbon (25 mg) under a nitrogen gas stream. The atmosphere in the reaction vessel was replaced five times with nitrogen gas, the reaction vessel was filled with hydrogen gas, and the system was stirred under a hydrogen gas stream for 24 hr. The mixture was filtered through Celite pad, and the catalyst was washed with ethanol (10 ml×2). The filtrate was concentrated under reduced pressure to give the title compound as an oil (90 mg, yield 99%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC1CCN
Reaction time: 9 h
Yield: 96.4 %

Procedure:
A suspension of 43.0 g of tert-butyl 2-(2-azidoethyl)-1-piperidinecarboxylate and 2.15 g of 5% palladium on carbon in 215 ml of methanol was catalytically hydrogenated at room temperature for 9 hours. After the reaction, the catalyst was filtered off, and the filtrate was concentrated to give 37.2 g of a colorless liquid.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:48])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>[Pt]=O.CO>[Cl:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1cccc(Cl)c1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=[Pt]
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Product: O=c1[nH]nc(CCc2c(F)cccc2Cl)cc1O
Yield: 24.8 %

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(2-chloro-6-fluorophenyl)ethynyl]pyridazine (Intermediate 32) except that the catalyst used for the hydrogenation was platinum oxide and the solvent was methanol and the final material was purified by preparative HPLC (0.035 g, 24.8% yield).
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:6][CH:5]=1)=[CH:2][CH3:3]>C1C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CC=Cc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCCc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
A solution of (cis- and trans-) ethyl 5-(1-propenyl)-1-[2'(1-triphenylmethyltetrazol-5yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate (350 mg, 0.53 mmol) in benzene (35 ml) containing 5% Pd/C (35 mg) in a Paar bottle was placed on a Paar apparatus under 40 psi H2 and shaken for about 4 hours at room temperature. The mixture was suction filtered through Celite and concentrated to leave 350 mg of a white solid. PG,105
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.CCOCC.[Cu]I.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>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C#CCO)cc1
Temperature: 50 °C

Procedure:
To a degassed solution of 1-bromo-4-tert-butylbenzene (5 g, 23.5 mmol) in tetrahydrofuran (25 mL) was added in the following order: copper(I) iodide (134 mg, 0.704 mmol), tetrakis(triphenylphosphine)palladium (813 mg, 0.704 mmol), and 1,8-diazabicyclo[5.4.0]-undec-7-ene (4.2 mL, 28.1 mmol). The resulting mixture was degassed again and a solution of propargyl alcohol (1.64 mL, 28.2 mmol) in tetrahydrofuran (2 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature over night. The mixture was diluted with ether (50 mL), washed with water (20 mL), 15% hydrochloric acid (2×20 mL) and saturated aqueous solution of sodium hydrogen carbonate (25 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1) affording 3-(4-tert-butylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19](S(C)=O)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:38][NH2:39].O1CCCC1>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19]([NH:39][CH3:38])=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(S(C)=O)nc32)CC1
Reactant: CN
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(NC)nc32)CC1

Procedure:
To a 100-mL round-bottomed flask was added Ethyl-4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-cyclohexanecarboxylate (820 mg, 1.52 mmol), dioxane(60 mL), then a 2 M solution of methylamine in tetrahydrofuran (7.6 mL, 15.2 mmol), and the solution was heated to 60° C. under an atmosphere of nitrogen for 5 hours. The solution was then concentrated in vacuo, and reacted further without purification: LRMS: 506.2 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:31]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[C:26]=3[CH:31]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCC(=O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of α-cyanoacetic acid (0.085 g., 1.0 mmol) in 2 mL dichloromethane was added oxalyl chloride (0.262 mL, 3.0 mmol) and one drop N,N-dimethylformamide (˜0.025 mL, cat). The solution is stirred for one hour, during which offgassing is observed, and concentrated in vacuo. The residue was dissolved in 4 mL dichloromethane and this solution was added dropwise to a solution of 6-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.275 g., 1.0 mmol) and triethylamine (0.152 mL, 1.1 mmol) in 3 mL dichloromethane at 0° C. The resulting solution was stirred for 2 hours, concentrated in vacuo and purified by flash chromatography to give 0.146 g (43%) of 3-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-oxo-propionitrile. MS: 343 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].F[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16]>C1COCC1>[CH3:3][O:4][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Using the procedure for Example 113C, in a 100 mL round bottomed flask, sodium hydride (276 mg. 11.5 mmol) was suspended in 30 ml, of a dry THF and cooled to 0° C. To this solution methanol (427 μL, 10.56 mmol) was added and stirred for 30 minutes. This solution 2-fluoro-4-nitro-1-trifluoromethyl-benzene (2.0 g, 9.6 mmol) was added as a 2 mL THF solution. The reaction was allowed to warm to room temperature overnight with stirring. The reaction was concentrated and then partitioned between ethyl acetate and water, extracting twice. The extracts were dried with magnesium sulfate, filtered and concentrated. The nitro compound was purified by silica gel chromatography using a gradient of ethyl acetate/hexane 0-50% over 60 minutes. The main peak was collected, and concentrated to afford 2-methoxy-4-nitro-1-trifluoromethyl-benzene as an oil weighing 1.16 g. 1H NMR (300 MHz, DMSO-d6) δ 8.0-7.9 (m, 3H), 3.9 (s, 3H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21]>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cc3ccccc3s2)cc(OC)c1OC

Procedure:
a-(2-benzo[b]thienyl)-3,4,5-trimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7m, 9.7 mmoles, 5.7 mls) and 3,4,5-trimethoxybenzaldehyde (8.9 mmoles, 1.8 g) in THF (20 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes, 2.4 g (97%) of a yellow-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[C:29]([S@:33]([NH2:35])=[O:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20]/[C:21](=[N:35]\[S@@:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:34])/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N(CCC/C(=N\[S@](=O)C(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Yield: 51 %

Procedure:
(S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (3.14 g, 7.04 mmol), (R)-t-Butylsulfinamide, Ti(OEt)4 (125 μL, 1.5 equiv) were mixed with dry THF (80 mL) and heated at reflux for overnight. LC-MS found most of starting material was consumed. The mixture was diluted with ether (200 mL), washed with water (50 mL), brine (30 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120-g silica gel cartridge, eluted with a 10˜35% EtOAc in hexanes gradient, to afford tert-butyl (S)-1-(4-bromophenyl)ethyl((E)-4-((R)-tert-butylsulfinylimino)-4-phenylbutyl)carbamate (1.97 g, 51%) product and recovered starting material (0.72 g). LC-MS Method 1 tR=2.43 min, m/z 549, 551 (M+1)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[C:25]([O:34][CH3:35])=[N:26][O:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN1CCCC1=O>[C:1]([NH:4][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][C:24]1[C:25]([O:34][CH3:35])=[N:26][O:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1onc(OC)c1CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1onc(OC)c1CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of diethyl acetamidomalonate (1.6 g, 7.4 mmol) and potassium tert-butoxide (0.9 g, 8.0 mmol) in N-methylpyrrolidone (30 mL) was stirred at room temperature for 30 min. Ethyl 4-(bromomethyl)-3-methoxyisoxazole-5-carboxylate (1.8 g, 6.8 mmol) in N-methylpyrrolidone (10 mL) was added (temp 22-28° C.) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured onto an ice/water mixture (100 mL) and the aqueous phase was extracted with EtOAc (3×150 mL). The organic extracts were washed with an aqueous solution of potassium tert-butoxide, water (100 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (silica gel, eluent: EtOAc/heptane=1:1) afforded crude title compound (1.8 g, 66%). A small sample was recrystallized (EtOAc/heptane) to give colourless crystals: mp 78-80° C. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 21.6 g of 2-(4-chlorophenyl)-4-quinolinol and 46 ml of phosphorus oxychloride was heated under reflux for 45 min., cooled to room temperature, and poured carefully onto 750 ml of ice water. This mixture was neutralized with 146 ml of 50% sodium hydroxide and extracted with 600 ml of methylene chloride in three portions. The extracts were combined, filtered through 15 g of Florisil, and concentrated in vacuo to leave 19.35 g of the above-named compound.
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][N:29]2[C:33](=[O:34])[N:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=3)[C:38]([O:40]C)=O)[CH:31]=[N:30]2)[CH2:27][CH2:26]1.C(N)C1C=CC=CC=1>>[CH2:6]([NH:7][C:38](=[O:40])[C:37]1[CH:42]=[CH:43][N:44]=[C:35]([N:32]2[C:33](=[O:34])[N:29]([CH2:28][CH:25]3[CH2:26][CH2:27]3)[N:30]=[CH:31]2)[CH:36]=1)[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: COC(=O)c1ccnc(-n2cnn(CC3CC3)c2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(-n2cnn(CC3CC3)c2=O)c1
Yield: 38 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate and with methyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate to react with benzylamine, N-benzyl-2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide was obtained as a colorless solid in 38% yield: mp 137-139° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.43 (s, 1H), 7.74-7.72 (m, 1H), 7.36-7.23 (m, 5H), 6.85 (br s, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.69 (d, J=6.9 Hz, 2H), 1.29-1.16 (m, 1H), 0.59-0.53 (m, 2H), 0.40-0.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.5, 151.2, 149.3, 147.9, 144.6, 137.3, 132.2, 128.9, 128.1, 127.9, 120.7, 109.3, 50.2, 44.4, 10.2, 3.6; MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@H:10]1[NH:18][C:17]2[C:12](=[N:13][C:14]([NH:19][CH:20]3[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[N:15][CH:16]=2)[N:11]1[CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@H:10]1[NH:18][C:17]2[C:12](=[N:13][C:14]([NH:19][CH:20]3[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]3)=[N:15][CH:16]=2)[N:11]1[CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1
Reactant: OC1CCC(N2c3nc(NC4CCC5(CC4)OCCO5)ncc3N[C@@H]2Nc2ccc(F)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(Nc2ncc3c(n2)N(C2CCC(O)CC2)[C@@H](Nc2ccc(F)cc2F)N3)CC1
Reaction time: 24 h
Yield: 1.9 %

Procedure:
4-[(R)-8-(2,4-Difluoro-phenylamino)-2-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-7H-purin-9-yl]-cyclohexanol (0.62 g, 1.7 mmol) was dissolved in 25 mL of methylene chloride under an N2 atmosphere. Trifluoroacetic acid (5 mL) was then added dropwise via addition funnel. After stirring for 24 h the resulting reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the resulting residue until pH 12. The basic aqueous layer was then extracted using chloroform (2×75 mL). The combined organic layers were dried with MgSO4. The crude product was then purified on the preparatory HPLC using a 5-70% CH3CN/H2O over 39 minutes method. Fractions of greater then 98% purity via analytical HPLC were combined and concentrated. Excess trifluoroacetic acid was removed by washing the product with 1.75 M potassium carbonate (3×100 mL). The organic layers were then concentrated to dryness under vacuum to give the ketone (0.015 g 0.033 mmol, 12%) as a fine white powder: LC-MS (m/z) 457.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([Cl:44])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:22][C:23]=2[C:24]([F:27])([F:26])[F:25])[C:16]#[N:17])=[CH:10][CH:9]=1.[BH4-].[Na+]>CCO.N.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([Cl:44])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:22][C:23]=2[C:24]([F:27])([F:26])[F:25])[CH2:16][NH2:17])=[CH:12][CH:13]=1
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cn1
Agent: Cl[Ni]Cl
Agent: N
Agent: [BH4-]
Solvent: CCO
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cn1

Procedure:
To a solution of 3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[6-[2-(3-methoxy propyl)phenyl]-4-(trifluoromethyl)pyridin-3-yl]propanenitrile from step 5 (1 eq.) in EtOH (0.05M) at 0° C. was added nickel chloride (NiCl2; 1 eq.) and then portionwise sodium borohydride (3 eq.). The final mixture was stirred for 2 h at room temperature, poured in conc. ammonia and extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with EtOAc/MeOH(NH3 2M) 10%, afforded the title compound as a colorless oil. 1H NMR (500 MHz, CD3OD): δ 8.91 (s, 1H), 7.63 (s, 1H), 7.44-7.32 (m, 4H), 7.19 (s, 2H), 7.02 (d, 2H), 6.80 (d, 2H), 4.34-4.27 (m, 4H), 3.56-3.49 (m, 1H), 3.27-3.15 (m, 6H), 3.11 (d, 2H), 3.06-2.99 (m, 1H), 2.80-2.70 (m, 2H), 2.29 (s, 3H), 1.71-1.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with Benzylamine to produce N-Benzyl-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21
Yield: 89 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride and sodium hydroxide solution. Yield: 89% of theory, C25H24N6O3 (456.5); EKA mass spectrum: (M+H)+=457; (M+Na)+=479.