Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].[OH-].[K+].Br[CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22]>CCO.Cl.C(O)(=O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Temperature: 90 °C
Yield: 41.7 %

Procedure:
To a solution of 1.12 g (4.8 mol) 2-acetyl-5-(trifluoromethyl)benzoic acid in EtOH (30 ml) were succesively added 270 mg (4.8 mmol) KOH and 1.15 g (4.8 mmol) diethyl 2-bromo-malonate at RT. The resulting mixture was heated at 90° C. for 6 h. After cooling to RT, the RS was concentrated in vacuo. The residue was taken up with water (30 ml) and extracted with EtOAc. The organic layer was washed with water (40 ml) and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with hydrochloric acid (10 ml) and acetic acid (6 ml) and the RS was heated at 90° C. for 2 h. After cooling to RT, the RS was poured into ice-water and the precipitate was filtered off to yield 540 mg (2.0 mmol, 41%) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O:23][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=O)[CH:25]=1.Cl>O1CCCC1>[CH3:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:26]2[CH2:27][CH2:28][CH2:29][C:24](=[O:23])[CH:25]=2)[C:20]1=[O:21]
Reactant: COC1=CC(=O)CCC1
Reactant: CN1CCCCCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1CCCCC(C2=CC(=O)CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Diisopropylamine (12.14 g, 17.0 ml) in dry tetrahydrofuran (THF 20 ml) was added dropwise to a stirred cooled (-10° C.) solution of butyl lithium (86 ml of 1.4 molar solution in hexane) under nitrogen. After 10 minutes Gilman test was negative. 1-Methylcaprolactam (14.19 g) in THF (20 ml) was added, also at -10° C. Reaction was stirred for 10 minutes at 0° C. and 3-methoxy-2-cyclohexenone (12.6 g, 0.1 mole) in THF (20 ml) was added. The mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours, then cooled to -10° C. and decomposed by addition of 2 N HCl (125 ml) rapidly but not allowing temperature to exceed 0° C. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to an oil which crystallised from toluene-light petroleum (b.p. 60°-80° C.) affording the title compound (18.99 g), m.p. 109°-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][CH:23]([F:35])[O:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH:23]([F:22])[F:35])[CH:26]=3)(=[O:33])=[O:32])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
4-(5-Amino-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.065 g, 0.222 mmol) was dissolved in 5 ml of pyridine. 3-(Difluoromethoxy)-benzene-sulfonylchloride (0.051 g, 0.212 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated, and the residue purified via silica gel chromatography using dichloromethane-methanol (0-20%) to yield to title compound (0.097 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C(C1C=CC=CC=1)C.[O:28]1[C:32]2([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:35]3([OH:38])[CH2:36][CH2:37][C:32]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:33][CH2:34]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc(-c2cscn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: OC1(c2nc(-c3ccccc3)cs2)CCC2(CC1)OCCO2
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
4.5 g of 4-phenylthiazole were dissolved in 80 ml of anhydrous THF and 18.1 ml of a 2 M solution of lithium diisopropylamide in THF/HEP/ethylbenzene (Aldrich) were added dropwise at −70° C. The mixture was stirred at −70° C. for 60 min, then a solution of 4.4 g of 1,4-dioxaspiro[4.5]decan-8-one in 50 ml of anhydrous THF was added dropwise at −65° C. to −70° C. Subsequently, the mixture was warmed to room temperature, poured onto 120 ml of a saturated aqueous sodium hydrogencarbonate solution and extracted three times with 80 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 7.1 g of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]3[CH2:27][CH:26]3[C:28]([O:30]C(C)(C)C)=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]3[CH2:27][CH:26]3[C:28]([OH:30])=[O:29])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CC1CCCCCSc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC1CCCCCSc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
96 mg (0.2 mmol) of tert-butyl 2-[5-(4,5-diphenylpyrimidin-2-ylsulfanyl)pentyl]-cyclopropanecarboxylate were dissolved in a mixture of 2 ml of dichloromethane and 2 ml of TFA and stirred at room temperature for 2 hours. The residue after removal of all volatile constituents in vacuo was purified by preparative HPLC (method A). 60 mg (87%) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH3:11][C:3]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][N:6]2[CH:8]=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2nncn2nc1Cl
Reactant: C1CCNCC1
Solvent: CCO
Product: Cc1cc2nncn2nc1N1CCCCC1

Procedure:
7.8 Grams (0.0462 mole) of the 6-chloro-7-methyl-s-triazolo[4,3-b]pyridazine is mixed with 7.86 grams (0.0924 mole) of piperidine in 50 ml of ethanol. The mixture is heated at reflux temperature for 4 hours. The mixture is concentrated by evaporation and the residue of the reaction mixture is partitioned between aqueous sodium bicarbonate solution and methylene chloride. The methylene chloride layer is separated, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The 7-methyl-6-piperidino-s-triazolo[4,3-b]pyridazine product is obtained as a residue from the evaporation. The product is recrystallized from hexane and found to melt at 78°-79° C. The structure of the product is confirmed by infrared spectroscopy, by nuclear magnetic resonance analysis, and by elemental analysis. (Calculated for C11H15N5 : C, 60.80; H, 6.96; N, 32.24. Found: C, 60.40; H, 6.98; N, 32.17.)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@:12]1([CH3:19])[C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:16]([C@:12]1([CH3:19])[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17]
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@]1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1

Procedure:
A solution of (S)-1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.50 g) in dichloromethane (30 mL) was treated with oxalyl chloride (0.65 mL) and 3 drops of N,N-dimethylformamide at ambient temperature for 1.5 hours. The mixture was concentrated and the crude material used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1.C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl piperidin-3-ylmethylcarbamate and diisopropylethylamine yielding tert-butyl (1-(3-nitropyridin-4-yl)piperidin-3-yl)methylcarbamate (99%). LCMS (m/z): 336.9 (MH+); LC Rt=2.27 min. 1H NMR (CDCl3): δ 8.80 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 6.85 (d, J=6.3 Hz, 1H), 4.63 (bs, 1H), 3.28-3.46 (m, 2H), 2.89-3.15 (m, 3H), 2.69-2.86 (m, 1H), 1.55-1.99 (m, 5H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1](OC1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C2C(=CC=CC=2)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:51].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Br:51][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [Br-]
Reactant: CCCCCCCC#CCCCCCOC1CCCCO1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Product: CCCCCCC/C=C\CCCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of alkyne 12 (150 mg, 0.509 mmol), quinoline (0.18 ml, 1.50 mmol) and Lindlar catalyst (Pd, 5% wt % on calcium carbonate, poisoned with lead, 100 mg) was stirred under a H2 atmosphere (balloon pressure) at room temperature for 3 h After removal of the solids residues by filtration through Celite, the filtate was washed with water and extracted with hexanes, dried MgSO4) and concentrated to afford a crude residue which was not purified. The residue was dissolved in dichloromethane at 0° C. and the mixture treated successively with triphenylphosphine (52 mg, 0.20 mmol) and triphenylphosphine dibromide (236 mg, 0.56 mmol) and the resultant mixture stirred for 1 h at 0° C. The mixture was then washed with 10% aq. potassium carbonate, water and dried (MgSO4). Concentration afforded a crude residue which was purified by flash column chromatography (eluent—hexanes) to afford the pure 8 (81%); δH(270 M CDCl3); 0.87 (3H, t, J=6.1 Hz), 1.1-1.65 (14H, m), 1.85 (2H, quin, J 7.0), 2.03 (4H, m), 3.4 (2H, t, J 6.8) and 5.35 (4H, m); δC(67.5 MHz, CDCl3) 27.06, 27.32 27.72, 27.91, 28.04, 28.96, 29.32, 29.37, 29.71, 29.83, 31.96, 32.82, 34.01, 129.31, 130.47.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])#[N:12].O>CN(C=O)C>[F:10][CH2:9][CH2:8][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12]
Reactant: FCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1OCCF
Temperature: 70 °C
Yield: 84.7 %

Procedure:
K2CO3 (1.74 g, 12.5 mmol) and 1-bromo-2-fluoro ethane (0.78 mL, 10.47 mmol) were added to a solution of 2-cyanophenol 134 (0.5 g, 4.19 mmol) in anhydrous DMF (10 mL), and heated at 70° C. for 45 min. After completion, the reaction mixture was cooled to room temperature and water (10 mL) was added and the mixture extracted with diethyl ether. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=2:1) to give the compound 135 (0.586 g, 84%) as a white solid. 1H NMR (CDCl3, 300 MHz) d 7.51-7.58 (m, 2H), 6.98-7.07 (m, 2H), 4.89 (t, J=3.9 Hz, 1H), 4.73 (t, J=4.2 Hz, 1H), 4.40 (t, J=3.9 Hz, 1H), 4.31 (t, J=3.9 Hz, 1H). HRMS calculated for C8H7NOF (M+H)+: 152.0513. found 152.0539.
Reaction SMILES: C(O)(=[O:3])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH2:31][C@@H:32]3[C@H:42]([C@H:43]([C:49](C)(C)C)CO[SiH](C)C)[C:41](=[O:53])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])=[CH:25][CH:24]=1>C1COCC1>[N:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH2:31][C@@H:32]3[C@@H:42]([C@H:43]([OH:3])[CH3:49])[C:41](=[O:53])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])=[CH:25][CH:24]=1
Reactant: CC(=O)O
Reactant: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@H]([C@@H](CO[SiH](C)C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 62 h
Yield: 21 %

Procedure:
3.69 ml (64.5 mmol - 10 equivalents) of glacial acetic acid and 19.3 ml (19.3 mmol - 3 equivalents) of a 1M solution of tetrabutylammonium fluoride in THF were added to a solution, which had been cooled to 0° C., of 2.97 g (6.5 mmol) of allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]carbapen-2-em-3-carboxylate in 60 ml of THF. The cooling bath was removed and the reaction solution was allowed to stand at room temperature for 62 h. To work up, it was poured a into a mixture of cold, saturated NaHCO3 solution and ethyl acetate, extraction with ethyl acetate was carried out, followed by washing with saturated NaHCO3 and NaCl solutions and drying over MgSO4. After evaporation of the solvent in vacuo and chromatography of the residue on 360 g of silica gel (toluene:ethyl acetate 9:1), 472 mg (21%) of the title compound were obtained as an oil, Rf: 0.24 (toluene:ethyl acetate 9:1).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[NH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([C:12]2[NH:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])[CH:13]=2)[CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92080.2 %

Procedure:
To a stirred solution of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (1 g, 0.00340 mol) in DMF (5 mL) was added DIPEA (1.976 g, 0.01529 mol), HOBt (0.574 g, 0.00425 mol) and EDCI.HCl (0.814 g, 0.00425 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.498 g, 0.00357 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried. The crude product was recrystallized from ethyl acetate to afford 0.54 g (36%) of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid ethyl ester. LCMS: 380.15 (M+1)+, 92.05%. To a stirred solution of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.54 g, 0.00136 mmol) in a mixture of THF (50 mL), methanol (25 mL) and H2O (25 mL) was added LiOH.H2O (0.18 g, 0.0042 mol) at ambient temperature. The resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water, acidified with concentrated HCl solution. The resulting precipitate was isolated by filtration and dried afford 0.44 g (92%) of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid. LCMS: 352.12 (M+1)+, 97.85%,
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:26][CH:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:35])(=[O:34])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[BH4-].[Na+]>CO>[OH:33][CH:30]1[CH2:31][CH2:32][CH:27]([CH2:26][CH:16]([C:13]2[CH:12]=[CH:11][C:10]3[S:9](=[O:35])(=[O:34])[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:2]([CH3:1])[C:15]=3[CH:14]=2)[C:17]([NH:19][C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)=[O:18])[CH2:28][CH2:29]1
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(=O)CC3)C(=O)Nc3ccn(C)n3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(O)CC3)C(=O)Nc3ccn(C)n3)cc21
Temperature: 25 °C

Procedure:
50 mg of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(4-oxocyclohexyl)propionamide are suspended in 20 ml of methanol, and 3.8 mg of sodium borohydride are added at room temperature. The mixture is stirred at room temperature for another hour. During the duration of the reaction, a clear solution slowly forms. The methanol is removed under reduced pressure, and the residue is extracted with ethyl acetate and water. The organic phase is washed twice with water and then dried over MgSO4 and concentrated under reduced pressure. The residue is lyophilized. This gives 42 mg of 3-(4-hydroxycyclohexyl)-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)C(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)NCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The oxime, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-ethoxyimino)-methyl]-benzamide (28.8 mg, 47.3 μmol) obtained in Step A was suspended in methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 μl) were added thereto at room temperature. The mixture was stirred at room temperature for 2 hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture, which was then extracted with methylene chloride (2×10 ml). The combined organic layers were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (methylene chloride/methanol (40:3)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-ethoxyamino)-methyl]-benzamide (Compound C-35, 20.5 mg, 71%) as a colorless syrup.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1CC[CH2:17]1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3([OH:15])[CH2:17][CH:14]=[CH:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C=CCC(O)C1CCC2(CC1)OCCO2
Reactant: C1CNC1
Solvent: ClCCl
Product: OC1(C2CCC3(CC2)OCCO3)CC=CC1
Temperature: 40 °C

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)but-3-en-1-ol (840 mg, 3.33 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (185 mg, 0.218 mmol) in DCM was degassed and heated to 40° C. under argon for 4 hours. After extraction with saturated NaHCO3 solution, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([CH3:20])[N:11]=[C:12]2[C:17](Cl)=[N:16][C:15]([CH3:19])=[N:14][C:13]=12.[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(#N)C>[NH2:23][CH2:22][CH2:21][NH:24][C:17]1[C:12]2=[N:11][N:10]([CH3:20])[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[C:13]2[N:14]=[C:15]([CH3:19])[N:16]=1
Reactant: Cc1nc(Cl)c2nn(C)c(-c3c(Cl)cccc3Cl)c2n1
Reactant: NCCN
Solvent: CC#N
Product: Cc1nc(NCCN)c2nn(C)c(-c3c(Cl)cccc3Cl)c2n1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-(2,6-dichlorophenyl)-7-chloro-2,5-dimethylpyrazolo[4,3-d]pyrimidine (652 mg, 2.0 mmol) in acetonitrile (50 mL) at 50° C., add ethylene diamine (2.4 g, 40 mmol) in one portion. Maintain the reaction at 50° C. for 2 h, cool to ambient temperature and remove the volatiles by evaporation. Partition the residue between CH2Cl2 (50 mL) and 1N NaOH (50 mL) and extract the aqueous layer with CH2Cl2 (2×30 mL). Wash the combined organic extracts with water (30 mL), brine (30 mL), dry over MgSO4 and evaporate to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10]1[C:23]2[C:22](=O)[C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:21]1[C:22](=[N:8]2)[C:23]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: Nc1cccc(N)c1N
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2nc3c4ccccc4c4ccccc4c3nc12

Procedure:
10.1 g (82 mmol) of 1,2,3-triaminobenzene and 4.6 g (70 mmol) of 9,10-phenanthrenequinone were placed in a four-necked flask, to which 350 g of a solvent of acetic acid and methanol at 1:1 was added for dissolution, followed by reaction at a reaction temperature of 70° C. for 2 hours. After the reaction, the solvent was removed and the resulting product was washed with methanol to obtain the intended product.