Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=O)=[CH:19][CH:18]=1.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:25]([CH:26]=[CH:1][C:2]([C:4]3[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=3)=[O:3])=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1cccnc1Nc1ccc(Cl)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)C=Cc2cccnc2Nc2ccc(Cl)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 3,4,5-trimethoxyacetophenone (135 mg, 0.06465 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 mL) and stirred for 5 minutes. Then added 2-(4-chlorophenylamino)nicotinaldehyde (150 mg, 0.0.6465 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6ax) (232 mg, 85% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Yield: 43 %

Procedure:
100 g of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) were added to an aqueous solution of EstB (500 mL cell extract; ˜5 g total protein concentration). At a temperature of 25° C. the pH was kept at 7.0 by continuous addition of 5M aqueous NaOH. After 55% conversion (corresponds to 50.6 mL of NaOH consumption) the reaction was stopped by addition of 100 mL of ethyl acetate. 100 mL of 5M aqueous NaOH were added and the layers were separated. The aqueous layer was washed once with 100 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to give 43 g of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; ee=98%).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([NH:39][CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][NH:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CNc1ccc(N)cn1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in step 1.1) and 0.216 g (1.67 mmol) of 3-amino-6-(methylamino)pyridine (WO2005/028452) in 10 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.471 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([O-:8])=O.[K+].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][C@H:27]([C@H:31]([CH3:34])[CH2:32][CH3:33])C(O)=O>Cl.CN(C)C=O>[CH2:11]([O:10][C:4](=[O:9])[CH2:5][C:6](=[O:8])[C@H:27]([CH3:26])[C@H:31]([CH3:34])[CH2:32][CH3:33])[CH3:12]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC[C@@H](C)[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)[C@H](C)[C@H](C)CC
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a 1 L round bottom flask equipped with a nitrogen inlet was charged 22 g (230 mmol) of magnesium chloride, 39 g (230 mmol) of potassium ethyl malonate and 200 mL of dimethylformamide. The contents of the flask were stirred at 50° C. for 1 hour and then cooled to 35° C. In a separate 500 mL, nitrogen inerted flask was added 200 mL of dimethylformamide, 28.6 g (177 mmol) of carbonyl diimidazole and 20 g of (2R,3R)-2,3-dimethyl-pentanoic acid was dripped in over 30 minutes. When the gas evolution had ceased, the contents of the 500 mL flask were added to the 1 L flask. The reaction was stirred for 2 days at 35° C. The reaction was cooled to room temperature and diluted with 800 mL of 1N HCl. The aqueous solution was extracted 3× with 1 L aliquots of MTBE. The organic extracts were combined and extracted with 200 mL of saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give 31.74 g of the titled compound: 1H-NMR (CDCl3) 4.180-4.120 (m, 2H), 3.454 (s, 2H), 2.522-2.453 (q, 1H, J=7.018), 1.738-1.673 (m, 1H), 1.418-1.328 (m, 1H), 1.270-1.217 (m, 3H), 1.113-1.010 (m, 4H), 0.889-0.815 (m, 5H); MS (Ion Mode: APCI) m/z=201 [M+1]+.
Reaction SMILES: [ClH:1].[C:2]1([C@H:12]([NH:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[O:18])[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[Na+].O>CO>[ClH:1].[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[OH:18])[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NCCC(=O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one hydrochloride (V) (15.95 g, 39.104 mmol) is suspended in cold methanol (50 ml) at −10° C. and, subsequently, a solution of sodium borohydride (0.75 g, 19.610 mmol), 30% w/w aqueous sodium hydroxide (5.74 g, 43.014 mmol) and water (5 ml) is added slowly in order to keep the internal temperature below 0° C. The reaction mixture is stirred at 0° C. for 0.5 hrs and then quenched by addition of 30% w/w aqueous hydrochloric acid up to pH=1, followed by water (40 ml), and allowed to reach room temperature. The so-formed thick suspension is heated up to 50° C., stirred for 20 minutes and then cooled down to 5° C. The precipitate is filtered, washed with a 9:1 vol/vol water/methanol mixture (10 ml) and dried at 50° C. under vacuum. 14.69 g (35.841 mmol) of high quality (R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IXa) are obtained (yield: 91.7%; white powder).
Reaction SMILES: [CH2:1]1[O:13][C:4]2([C:9](Br)=[CH:8][C@H:7]3[CH2:11][O:12][C@@H:5]2[O:6]3)[O:3][CH2:2]1.C([Li])CCC.[CH2:19]=[O:20]>O1CCCC1>[CH2:1]1[O:13][C:4]2([C:9]([CH2:19][OH:20])=[CH:8][C@H:7]3[CH2:11][O:12][C@@H:5]2[O:6]3)[O:3][CH2:2]1
Reactant: BrC1=C[C@H]2CO[C@H](O2)C12OCCO2
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCC1=C[C@H]2CO[C@H](O2)C12OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1.65 g of 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal obtained in the above Intermediate Preparation Example 8 (1), was dissolved in 200 ml of dry tetrahydrofuran, and the solution was cooled to -78° C. Then, 5 ml (1.6N) of n-butyl lithium was gradually added thereto, and the mixture was further stirred for 20 minutes. To the obtained reaction mixture, formaldehyde gas was introduced in large excess, and the temperature was raised to room temperature. Termination of the reaction was confirmed by TLC, and then the reaction mixture was filtered through Celite® to remove the precipitate. The filtrate was concentrated under reduced pressure, and the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:1) to obtain 0.7 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal. The NMR analytical data of this product are as follows.
Reaction SMILES: [CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:32][C:31]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=2)=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-UN-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-hydroxyphenylacetyl)amino]-(R)-propionate 48d (1.5 g, 4.1 mmol) and 3,5-bistrifluoromethylbenzyl bromide (1.3 g, 4.2 mmol) in DMF (10 mL) was stirred at 60° C. overnight in the presence of K2CO3 (1.14 g, 8 mmol). After cooling to room temperature, EtOAc was added and the solution was washed with brine three times, dried over MgSO4, and concentrated. Purification on a silica gel column by eluting with 40% EtOAc/hexane afforded the product (1.46 g, 60%) as a solid. MS (CI—NH3): (M+H)+=592.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=C(F)C=2)=NOC=1C)=O)C>>[F:19][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)c1c(-c2ccc(F)c(F)c2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Product: Cc1onc(-c2ccc(F)c(F)c2)c1CO
Yield: 99.6 %

Procedure:
As described for example 88d, 3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (28.5 g, 107 mmol), instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, was converted to the title compound (24.0 g, 48%) which was obtained as a light yellow solid. MS: m/e=226.2 [M+H]′.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:36])=O>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:36])[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCCc1cnn2c(O)nc(SCc3ccccc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: N#CCCCCc1cnn2c(Cl)nc(SCc3ccccc3)nc12

Procedure:
A solution of compound (4) (6.0 g, 17.7 mmol) and N,N-dimethylaniline (2.24 mL, 17.7 mmol) in phosphorus oxychloride (20 mL) was heated to reflux in a sealed tube for 1 h. Solvent was removed and the residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3, dilute HCl, followed by brine, dried over anhydrous Na2 SO4, filtered and concentrated to give 5-(2-benzylsulfanyl-4-chloro-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (5), which was used directly for the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:27][C:8]1([CH3:28])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 45.5 %

Procedure:
To a solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (100 mg, 0.3 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at 80° C. for 6 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3); and the combined organics were dried over anhydrous Na2SO4 The solvent was removed in vacuo and purified by preparative HPLC to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 52%) as a yellow foam. MS (ESI+) [(M+H)+] 367.2.
Reaction SMILES: [CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:2]1.C(O)(=O)C.[BH4-].[Na+].CCOC(C)=O>C(Cl)Cl>[CH:1]1([C@H:4]2[C@H:8]([OH:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(=O)[C@@H]1C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O)[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (15) (4.0 g, 17.62 mmol) was dissolved in CH2Cl2 (90 mL) and acetic acid (10 mL) and cooled to 0° C. NaBH4 (1.33 g, 35.24 mmol) was added in several portions and the reaction stirred for 16 hr at rt. EtOAc (300 mL) was added and the organics were washed with sat. aq. NaHCO3 (300 mL), brine (200 mL), and dried over Na2SO4. Concentration of the solution in vacuo led to isolation of (2S,3R)-tert-butyl 2-cyclopropyl-3-hydroxy-5-oxopyrrolidine-1-carboxylate (16) (1.34 g, 33%) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])=[N:11][C:7]=2[CH:6]=1)=[NH:4].[C:30](Cl)(Cl)=[O:31]>>[CH3:27][CH:25]([CH3:26])[CH2:24][CH2:23][N:9]1[C:8]2[CH:28]=[CH:29][C:5]([C:3]3[NH:4][C:30](=[O:31])[O:1][N:2]=3)=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22]
Reactant: O=C(Cl)Cl
Reactant: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C(=N)NO)ccc21
Product: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(-c3noc(=O)[nH]3)ccc21
Reaction time: 48 h
Yield: 26.3 %

Procedure:
N-Hydroxy-1-(3-methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carboxamidine (75 mg, 0.191 mmol) was treated with phosgene (1 ml, 1.91 mmol, 1.92 M in toluene) and heated to reflux for 2.5 h. The mixture was cooled and stirred for 48 h. A white precipitate was isolated by filtration to give 21 mg (26%) of 1-[1-(3-Methyl-butyl)-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+:21]=[N-:22].CN(C)C(=[NH2+])N(C)C.C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[N:20]([CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:21]=[N-:22]
Reactant: CCOC(=O)C(=O)N(CCBr)N=Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CCN=[N+]=[N-])N=Cc1ccccc1

Procedure:
11 g. of the ethyl ester product from part (c) are added to acetone along with 5.7 g. of tetramethylguanidinium azide and 0.05 g. of 18-Crown-6. The mixture is refluxed for eight hours. After distilling off the solvent, the reaction mixture is stirred with 50 ml. of methylene chloride. The organic phase, after drying and concentrating, leaves an oil which crystallizes in the form of white crystals upon the addition of a small amount of isopropanol to yield [1-(2-azidoethyl)-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 59°-61°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20](Br)=[N:19][N:18]=[C:17]2[CH3:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:23]>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][C:17]1[N:16]2[C:5]3[C:6]([C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:23][C:20]2=[N:19][N:18]=1)=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3
Reactant: N
Reactant: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Cc1nnc2nc(-c3ccccc3)c3cc(Cl)ccc3n12
Temperature: 0 °C

Procedure:
In the next place, a solution of 0.5 g of the above-mentioned 5-chloro-2-(3-methyl-5-bromo-4H-1,2,4-triazol-4-yl)benzophenone in 20 ml of dimethylsulfoxide was heated, with stirring, at about 180° C for 10 hours, during which ammonia gas was continuously passed into the reaction mixture. After cooling, the reaction mixture was poured into ice-water and the resulting crystals were filtered, washed with water and dried. The crystals thus obtained was dissolved in chloroform and chromatographed on silica gel using chloroform as an eluent. The product thus separated was recrystallized from isopropyl ether to give 1-methyl-5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline, m.p. 325° - 327° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:28]1[C:32]2[CH2:33][CH2:34][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:36][C:31]=2[N:30]=[CH:29]1.ClCCl>O>[C:9]([N:28]1[C:32]2[CH2:33][CH2:34][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:36][C:31]=2[N:30]=[CH:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C1CCc2[nH]cnc2C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Triethylamine (4.7 ml) and chlorotriphenylmethane (9.37 g) were added to a mixture of methyl 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylate (6.73 g) and dichloromethane (70 ml), followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with dichloromethane, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain a mixture (10.13 g) of methyl 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylate and methyl 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-6-carboxylate. Methanol (50 ml), water (20 ml) and sodium hydroxide (4.78 g) were added to the obtained mixture, followed by heating to reflux overnight. The reaction solution was concentrated, water and concentrated hydrochloric acid (8 ml) were added to the residue, and the precipitated solid was collected by filtration, washed with water and acetone and dried under reduced pressure to obtain a mixture (7.07 g) of 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-6-carboxylic acid, as a colorless solid.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:18][CH2:17][C:8]2[N:9]=[C:10]([N:12]=CN(C)C)[S:11][C:7]=2[C:6]1=O)C.[N+]([O-])(O)=O.[C:24]1([NH:30][C:31]([NH2:33])=[NH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[C:24]1([NH:30][C:31]2[N:33]=[CH:4][C:5]3[CH2:18][CH2:17][C:8]4[N:9]=[C:10]([NH2:12])[S:11][C:7]=4[C:6]=3[N:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C=Nc1nc2c(s1)C(=O)C(=CN(C)C)CC2
Reactant: N=C(N)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Nc1nc2c(s1)-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 100 °C
Yield: 7.5 %

Procedure:
A mixture of N′-(6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-N,N-dimethyl-formamidine (200 mg, 0.72 mmol), N-phenyl-guanidine nitrate (142 mg, 0.72 mmol), NaOH (57 mg, 1.44 mmol) and 2-methoxyethanol (4 mL) was heated under microwave irradiation (300 W, 100° C.) for 30 min. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) afforded the title product as a dark yellow solid (16 mg, 8%): mp 240° C. (dec). 1H-NMR (DMSO-d6): δ 9.42 (s, 1H, NH), 8.23 (s, 1H, Py-H), 7.77 (d, 2H, J 7.7, Ph-H), 7.26 (t, 2H, J 7.7, Ph-H), 6.91 (t, 1H, J 7.2, Ph-H), 2.93 (s, 4H, CH2—CH2). MS (ESI+): m/z 296.07 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[NH2:13][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C(=O)OC(C)(C)C)n1
Agent: [Pd]
Product: COC(=O)c1cc(N)n(C(=O)OC(C)(C)C)n1

Procedure:
A mixture of 1.0 eq. of 19 and 0.1 wt/wt eq. of 10% Pd on carbon was hydrogenated at 10-60 psi of hydrogen for a time sufficient for reaction completion. The reaction mixture was filtered through Celite. The filtrate was concentrated by rotary evaporation. The crude material was dried under vacuum to give product 20.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2.[O:19]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:19][C:7]([CH3:17])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:18])[C:14]([NH2:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(N)=O)=C(C)C1=O
Yield: 79.2 %

Procedure:
Oxidation as described in protocol B, using 186 mg (0.747 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 907 mg CAN (1.65 mmol) yielded 157 mg of 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:26])[N:10]([O:27]CC3C=CC=CC=3)[C:9]2=[O:35])[CH:5]=[CH:6][CH:7]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH:16]=3)[C:11](=[O:26])[N:10]([OH:27])[C:9]2=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cccc(F)c2)CC1
Agent: [Pd]
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2cccc(F)c2)CC1
Yield: 65.9 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.07 g) with 1-(3-fluorophenyl)-6-fluoro-3-benzyloxy-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example Z-1, 0.209 g, 0.43 mmol) provided 0.11 g of the title compound as a solid, mp 176-178° C.