Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[C:47]([CH3:53])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[C:47]([CH3:53])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Cc1cc(N)ccc1C#N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Cc1cc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)ccc1C#N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-2-methyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=394.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1>C(Cl)Cl>[N:10]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:18])[CH3:1])=[CH:8][CH:7]=2)[N:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: CN(C)c1ccc(N=Nc2ccccc2N)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(-n2nc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
In CH2Cl2 was dissolved 8a (1g, 1 eq) and a solution of Pb(OAc)4 (2.03 g, 1.1 eq) in which CH2Cl2 was added dropwise. The resulting solution was stirred 30 min at RT, then hydrolyzed with 1 5 ml of Na2CO3 salt, extracted with CH2Cl2, dried by Na2SO4, evaporated and purified by flash chromatography (SiO2, hexane/AcOEt, 8/2) giving 9a as an orange solid in 37% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8](=[CH:12][CH:13]=1)[C:9]([NH2:11])=[O:10])([O:3][CH3:4])=[O:2].Cl[C:16]1[S:17][CH:18]=[CH:19]N=1>>[S:17]1[C:16]2=[N:14][C:7]3[C:8]([C:9](=[O:10])[N:11]2[CH:19]=[CH:18]1)=[CH:12][CH:13]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[CH:6]=3
Reactant: COC(=O)c1ccc(C(N)=O)c(N)c1
Reactant: Clc1nccs1
Product: COC(=O)c1ccc2c(=O)n3ccsc3nc2c1
Yield: 78.1 %

Procedure:
19.4 g of 4-carbomethoxyanthranilamide and 12 g of 2-chlorothiazole were stirred for 4 hours at 150° C. After working up in the conventional manner there was obtained 20.3 g (78%) of the above compound; m.p. 228°-230° C.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:23]1=2.Cl>C1COCC1.CC(OC)(C)C.O>[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])[CH:30]=[CH:31][C:23]1=2
Reactant: Br[Mg]c1ccc2c(c1)OCCO2
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCCO2
Temperature: -17.5 °C
Reaction time: 17 h

Procedure:
A suspension of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of Argon and cooled down to −15 to −20° C., isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol) was added keeping the temperature below −10° C. The slurry started to dissolve, temperature was allowed to reach 0° C., a freshly prepared solution of (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t., the reaction mixture was stirred for 17 h. 1N HCl (300 mL) was cooled on icebath to +10° C., the reaction mixture was poured into the acidic water solution, TBME=tert-butyl methyl ether (300 mL) was added and the mixture was transferred to a separation funnel. The waterphase was backextracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na2SO4).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14](Cl)=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[N-:27]=[N+:28]=[N-:29].[Na+]>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14]([N:27]=[N+:28]=[N-:29])=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc2oc(C(=O)N=[N+]=[N-])cc(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
3.1 g of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride was dissolved in 80 ml of anhydrous tetrahydrofuran. This solution was dropwise added to 10 ml of an aqueous solution containing 1.26 g of sodium azide in 10 minutes at 5°-10° C. The mixture was stirred for 1.5 hours at 10°-20° C. The resulting crystal was collected by filtration to obtain 1.45 g (yield: 46%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid azide having a melting point of 146°-149° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:35])[CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[CH:16][CH:15]=4.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1([CH3:42])[C:10]2=[CH:11][C:12]3[N:13]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:35])[CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[CH:16][CH:15]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc(-c4cccc(C(=O)c5ccccc5)c4)c2)cc13
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5cccc(-c6cccc(C(=O)c7ccccc7)c6)c5)ccc4n(-c4ccccc4)c3cc21
Temperature: 45 °C
Yield: 67.6 %

Procedure:
9.6 g (17.9 mmol) of [3′-(12,12-dimethyl-10,12-dihydro-10-azaindeno-[2,1-b]fluoren-7-yl)biphenyl-3-yl]phenylmethanone are dissolved in 300 ml of toluene with 3.14 g (20 mmol) of bromobenzene and degassed. 1.9 ml of tri-tert-butylphosphine solution (1 M in toluene), 214 mg (0.94 mmol) of Pd(OAc)2 and 5.4 g (56.7 mmol) of NaOtBu are added, and the mixture is stirred under reflux for 7 h. The warm (45° C.) mixture is filtered through Alox B, washed with water, dried and evaporated. The crude product is extracted with toluene in a Soxhlet extractor and recrystallised from toluene/heptane, giving 7.4 g (12.1 mmol, 60%) of the product as a white solid. Finally, the product is sublimed in a high vacuum, the purity is 99.9%.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][C@H:28]([CH3:30])[NH:27][CH2:26][C@@H:25]1[CH3:31].C(O)(C)C>Cl>[C:1]1([C:7]2[N:16]=[C:15]([N:27]3[CH2:26][C@H:25]([CH3:31])[N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:29][C@@H:28]3[CH3:30])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H]1CN(c2ccccn2)[C@@H](C)CN1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: C[C@H]1CN(c2nc(-c3ccccc3)nc3ccccc23)[C@@H](C)CN1c1ccccn1
Temperature: 25 °C

Procedure:
A mixture containing 8.4 g (0.03 mole) of 2-phenyl-4-chloroquinazoline, 6.3 g (0.0335 mole) of 1-(2-pyridyl)-cis-2,5-dimethylpiperazine and 200 ml of isopropanol was refluxed for 6 hrs. The resulting reaction mixture was filtered after cooling to room temperature. A crystalline solid was obtained. The crude product was dissolved in 3N hydrochloric acid and extracted with ether. The aqueous acidic solution was adjusted to pH=7.5 and filtered. Yield of crystalline solid was 4.3 g, m.p. 68°-70° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[O:6]1)=[O:4].I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[Cl:33]>>[Cl:33][C:23]1[CH:24]=[C:25]([O:28][C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH:13]=1
Reactant: FC(F)(F)Oc1ccc(OCCCI)c(Cl)c1
Reactant: CCC1(C(=O)OC)Cc2ccc(O)cc2O1
Product: CCC1(C(=O)O)Cc2ccc(OCCCOc3ccc(OC(F)(F)F)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Step 2 and the iodide prepared in Example 3, Step 2.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:25][C:22]4[CH:23]=[CH:24][C:19]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:20][CH:21]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc(-c5ccccc5)cc4)c23)c1
Temperature: 50 °C

Procedure:
Under a nitrogen atmosphere, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 273 mg (1.5 mmol) of biphenyl-4-carbaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour. 440 mg (7 mmol) of NaCNBH3 are then added and the reaction mixture is heated to 50° C. After 15 hours a further 440 mg of NaCNBH3 are added and the reaction mixture is stirred at boiling temperature for 15 hours, then poured into 0.6 liter of a 1% aqueous K2B4O7.4H2O solution and stirred overnight to complete the reaction. The precipitated product is filtered off and washed with water. Heating in 20 ml of ethanol and filtration yield 4-(3-chloro-phenylamino)-3-(4-phenyl-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 250-252° C.; HPLC: tRet(grad20-100/20=14.1; FAB-MS: (M+H)+=427.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7]3[C:12]([NH:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[C:9]([N+:16]([O-])=O)[CH:8]=3.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[OH-].[Na+].C(=O)(O)[O-].[NH4+]>C(O)C.O>[NH2:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:15]=3)[C:6](=[O:19])[C:7]=2[CH:8]=1
Reactant: Nc1ccc2c(=O)c3cc([N+](=O)[O-])ccc3[nH]c2c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(=O)c3cc(N)ccc3[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Finely ground 3-amino-7-nitro-9(10H)-acridone (AR-ACO-7, 22.50 g, 88.1 mmol) was suspended in ethanol (950 mL) and stirred at reflux. A solution of sodium sulfide nonahydrate (94.75 g, 394 mmol) and sodium hydroxide (37.5 g, 938 mmol) in water (1.7 L) was added in one lot and refluxing continued for 20 hr. The mixture was allowed to cool to room temperature and ammonium bicarbonate (50 g) was added in one lot and dissolved. The solution was reduced to about 500 mL on a rotary evaporator and allowed to stand overnight. The flask was chilled with ice-water, the product collected, and washed with ice cold water until the filtrate was a pale yellow-green colour. The crude product was dried then dissolved in boiling 1 M hydrochloric acid (900 mL). Charcoal (1 g) was added and the solution filtered whilst hot through a fluted paper. The filtrate was basified to pH 8 by the addition of 0.88 s.g. ammonia and the precipitate collected and was washed with water (2×20 mL) and dried over P2O5 under vacuum to yield a yellow solid AR-ACO-08 (19.85 g, 61.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:34])([C@@H:14]([CH:21]([OH:33])[C:22]4[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=4)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:34])([C@@H:14]([C:21]([C:22]4[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=4)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:33])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(C(=O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above ethyl 3-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)benzoate was dissolved in anhydrous methylene chloride (5 mL). Pyridine (0.1 mL) and Dess-Martin periodinane (215 mg, 0.51 mmol) were added. The reaction mixture was stirred at RT for 40 min before saturated aqueous sodium bicarbonate solution (6 mL) and saturated aqueous sodium thiosulfate solution (3 mL) were added. The mixture was stirred at RT for 20 min. The aqueous layer was separated and extracted with methylene chloride (2×2 mL). The combined organic solutions were dried (Na2SO4). Silica gel flash chromatography (20-100% ethyl acetate in heptanes, then 0-20% methanol in ethyl acetate) gave ethyl 3-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbonyl)benzoate as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:28](OC)([O:31]C)[O:29]C.[NH4+].[Cl-]>C1COCC1.O>[CH3:19][C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:11]1[CH3:22])=[O:16])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 103.8 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazine carboxylate (1.8 g, 4.9 mmol) in THF (4.9 mL) was mixed with nBuLi (3.7 mL, 1.6 M in Hexane, 5.9 mmol) at −78° C. and stirred for 30 min before B(OMe)3 (2.2 mL, 19.6 mmol) was added. After addition, the resulting solution was warmed up to room temperature within 2 hours. The mixture was then mixed with saturated aqueous NH4Cl solution (10 mL), stirred for 25 minutes at room temperature, diluted with H2O (5 mL) and extracted with Et2O (2×30 mL). The organic layers were collected, dried over Na2SO4, filtered and concentrated to afford the crude title compound (1.7 g, quantitative yield): LC/MS: m/z 335 (M+H); 1H-NMR (MeOD) δ 1.24 (d, 3H), 1.46 (s, 9H), 2.00 (m, 1H), 2.13 (m, 1H), 2.68 (d, 1H), 2.82 (d, 1H), 3.12 (m, 1H), 3.44 (m, 1H), 3.56 (m, 1H), 3.80 (d, 1H), 4.18 (m, 1H), 7.33 (m, 1H), 7.38 (m, 1H), 7.51 (d, 1H), 7.59 (s, 1H).
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([C:18]([OH:20])=[O:19])[NH2:17].[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[C:21]1(=[O:26])[N:17]([CH:16]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH3:15])[C:2]=3[O:20][C:18]2=[O:19])[C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12
Reactant: Cc1ccccc1Oc1cccc(C(N)C(=O)O)c1O
Reactant: O=C1OC(=O)c2ccccc21
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2N1C(=O)c2ccccc2C1=O
Temperature: 200 °C
Yield: 12.1 %

Procedure:
A mixture of 2-[2-hydroxy-3-(o-tolyloxy)phenyl]glycine (10.6 g) and phthalic anhydride (5.7 g) was heated in an oil bath (200° C.) for 5 minutes. After cooling, the reaction mixture was subjected to column chromatography on silica gel (280 g) and eluted with benzene to give 3-phthalimido-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (1.8 g). mp 168°-170° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:28][CH:27]=1.[C:50]1([CH:56]([C:67]([O-])=[O:68])[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:35]([N:34]=[C:33]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:67](=[O:68])[CH:56]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:31][CH:30]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(CN)cc1
Reactant: O=C([O-])C(C(=O)OCc1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(CNC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBTU (88 mg; 0.274 mmol) was added to a solution of 1-[4-(aminomethyl)phenyl]-2,3-di-tert-butyloxycarbonyl-guanidine hydrochloride (8) (100 mg; 0.249 mmol), monobenzyl 2-phenylmalonate (67.3 mg; 0.249 mmol), HOBt (37 mg; 0.274 mmol) and triethylamine (104 μl; 0.747 mmol) in DMF (5 ml), and the solution was stirred at room temperature overnight. After stripping off the solvent under reduced pressure, the residue was taken up in ethyl acetate (20 ml) and washed 3× with 5% NaHCO3 solution, 3× with 0.5 M HCl and 1× with saturated NaCl solution. The organic phase was dried (Na2SO4) and the solvent was stripped off under reduced pressure. The product was recrystallized from ethanol/water.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH:5]([C:7]([S:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)=[S:8])[NH2:6].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:24][C:21]([C:12]1[CH:11]=[C:10]([S:9][C:7]2[S:8][C:1](=[S:2])[NH:6][N:5]=2)[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]=1[OH:20])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(SC(=S)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Sc2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Thiophosgene (0.37 mL, 4.8 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl hydrazinecarbodithioate (1.5 g, 4.8 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid which is crystallized from ethyl acetate/hexane to afford 1.5 g (88%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1,3,4thiadiazole-2(3H)-thione, mp 181.0°-185.5° C.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>CN(C)C=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(=O)N(Cc1ccccc1O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 666 mg of N-acetyl-N-(2-hydroxybenzyl)-2-phenoxyaniline in 10 ml of N,N-dimethylformamide was added 80 mg of 60% NaH/oil, followed by stirring at room temperature for 30 minutes. To this was added 0.3 ml of methyl bromoacetate, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into 0.5 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude N-acetyl-N-(2-methoxycarbonylmethoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1>O=[Pt]=O.CO>[NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Agent: O=[Pt]=O
Solvent: CO
Product: N#Cc1cc(N)c(N)cc1F
Yield: 100 %

Procedure:
A mixture comprising 2,4-difluoro-5-nitrobenzonitrile (9.03 g, 0.049 mol) and ethanol (10-15 mL) was stirred at ambient temperature while concentrated ammonium hydroxide (40 mL) was slowly added to give a precipitate. The precipitate was isolated by filtration and lyophilized to give 4-amino-2-fluoro-5-nitrobenzonitrile (7.84 g, 0.043 mol) as an off-white solid; PB-CI/MS: 182=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 6.856(d, 1H), 8.22(bs, 2H), 8.577(d, 1H). A mixture of 4-amino-2-fluoro-5-nitrobenzonitrile (3 g, 0.017 mol), PtO2 (≈300 mg) and methanol (20 mL)was hydrogenated (1 atm) for approximately 12 hours, filtered over celite and concentrated to dryness to provide 4,5-diamino-2-fluorobenzonitrile (2.5 g, 0.017 mol) as a brown solid PB-CI/MS: 152=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 4.7(bs, 2H), 5.863(bs, 2H), 6.375(d, 1H), 6.56(d, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([OH:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]2[CH:11]=[C:10]3[O:12][CH2:14][CH2:15][CH2:16][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: Oc1cc(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(-c2cc3n(n2)CCCO3)cc1

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-ol (8.80 g, 0.055 mol), 1-bromo-3-chloropropane (9.5 g, 1.1 eq, 0.06 mol) and potassium carbonate (30.3 g, 4 eq, 0.22 mol) in acetonitrile (120 mL) is heated for 5.5 h under reflux. Thereafter the volatiles are evaporated and the residue is treated with 50 mL ethyl acetate. The residual solid is washed 2× with ethyl acetate and the combined organic phases are evaporated. The obtained crude product is triturated with methyl tert butylether and 6.4 g (53%) of 2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained as solid.