Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:6]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:44]=[C:45]([CH:57]=[CH:58][C:59]=1[F:60])[CH2:46][C:47]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]1>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]1([CH:6]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)[C:7]([NH:42][C:43]2[CH:44]=[C:45]([CH:57]=[CH:58][C:59]=2[F:60])[CH2:46][C:47]2([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH2:49]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC1CCN(C(C(=O)O)C2=CCCC2)CC1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)OC(C)(C)C)CC3)ccc2F)C2=CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.9 mg (0.13 mmol) of rac-cyclopent-1-en-1-yl(4-methoxypiperidin-1-yl)acetic acid were initially charged in 0.87 ml of DMF/pyridine (3:1), 63.8 mg (0.17 mmol) of HATU were added and the mixture was stirred at RT for 30 min 34.3 mg (0.13 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were then added, and the reaction mixture was stirred at RT overnight. The mixture was then diluted with ethyl acetate, washed repeatedly with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC (RP18 column; acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min). This gave 20.7 mg (33% of theory) of the title compound.
Reaction SMILES: C([O:9][CH2:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([N:20]3[CH2:24][CH:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])[CH:17]=[CH:16][C:14]=2[N:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O1CCOCC1>[OH:9][CH2:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([N:20]3[CH2:24][CH:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])[CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: COCC1CN(c2ccc3nc(COC(=O)c4ccccc4)sc3c2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COCC1CN(c2ccc3nc(CO)sc3c2)C(=O)O1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
4.7 g of the 3-(2-benzoyloxymethylbenzothiazol-6-yl)-5-methoxymethyl-2-oxazolidinone obtained in the Example 1 was dissolved in methanol/dioxane (1:1) solvent. 7.5 ml of a 2N NaOH aqueous solution was added to the solution and the mixture was stirred for 2 h. Methanol was removed under reduced pressure and then water was added to the residue. After extraction with ethyl acetate followed by drying over sodium sulfate, the solution was concentrated under reduced pressure to give 3.25 g of the titled compound.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.NC1C=CC=CC=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[S:40])=[C:34]([CH3:41])[CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([CH3:41])[CH:33]=1)#[N:31].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:40]2)=[C:34]([CH3:41])[CH:33]=1)#[N:31]
Reactant: CCC(C)[C@H](N)CO
Reactant: Cc1cc(C#N)ccc1N=C=S
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Solvent: Nc1ccccc1
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)cc2C)N1
Product: Cc1cc(C#N)ccc1N

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-methylaniline was synthesized as described in Method A1a. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate as described in Method A2a, Step 3. 4-Cyano-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-methylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[H][H].CCN(CC)CC>CCO.C1COCC1.[Pd]>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2nc3cccnc3nc2-c2ccc(C)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Reaction time: 48 h

Procedure:
A solution of 2,3-dip-tolylpyrido[2,3-b]pyrazine (step 1)(181 g, 487 mmol) in EtOH/THF (1:2, 2100 ml) was treated with 10% palladium on carbon (30 g, 28.8 mmol) and the reaction mixture was placed under 0.1 bar of hydrogen at RT. After 2 days and 4 days respectively, additional batches of 10% palladium on carbon (10 g, 9.6 mmol, twice) were added along with Et3N (85 ml, 706 mmol, twice). After 7 days in total, the reaction mixture was filtered through Hyflo (filter material) and washed through with THF (2.5 L in portions). The filtrate was concentrated in vacuo to give a green/yellow solid. The solid was triturated with 1:1 TBME/heptane (500 ml) and filtered. The solid was washed with 1:1 TBME/heptane (200 ml) to give a pale yellow solid which was dried overnight to afford the title compound; HPLC (Agilent 1200), Rt 4.73 min, Method B.
Reaction SMILES: [OH-:1].[K+].O[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH2:13](Br)[CH:14]=[CH2:15]>CC(C)=O.CCCCCC>[CH2:13]([C:11]1[C:12]([OH:1])=[C:7]([C:5](=[O:6])[CH3:4])[CH:8]=[CH:9][CH:10]=1)[CH:14]=[CH2:15]
Reactant: C=CCBr
Reactant: [OH-]
Reactant: O=C(CO)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=CCc1cccc(C(C)=O)c1O
Temperature: 165 °C
Yield: 77.4 %

Procedure:
A suspension of 6.2 g of potassium hydroxide, 10 g of 2-hydroxyacetophenone and 17.8 g of allyl bromide in 550 ml of acetone was refluxed for 16 hours, cooled and filtered. The solids were extracted with three 250 ml portions of chloroform and the combined acetone filtrate and chloroform extracts concentrated to give a residue which was then heated at 165° C. for 18 hours, cooled, diluted with 250 ml of hexane and filtered. The resulting filtrate was concentrated in vacuo to give 10.02 g of 3'-allyl-2'-hydroxyacetophenone as a liquid: TLC Rf 0.70 in 3:1 toluene-methyl isobutylketone; C-13 NMR (CDCl3): δ26.72, 33.41, 116.0, 118.44, 119.21, 128.82, 129.34, 136.10, 136.44, 160.40, 204.75; 1H-NMR (CDCl3): δ2.60 (s, 3H), 3.40 (d, J=6.4 Hz, 2H); 5.05 (d, J=1.4 Hz, 1H), 5.08-5.11 (m, 1H), 5.92-6.06 (m, 1H), 6.82 (t, J=7.6 Hz, 1H), 7.33 (d, J=6.7 Hz, 1H), 7.59 (d, J=6.7 Hz, 1H), 12.62 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1)[CH3:23]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(O)c1

Procedure:
A mixture of 3-hydroxy-4-methylbenzoic acid (25.42 g, 167 mmol) (TCI US) and concentrated sulfuric acid (3 mL) in absolute ethanol (180 mL) was heated at reflux for 20 hours. After cooling, solid sodium bicarbonate (10 g) was added to neutralize the acid. Mixture was partitioned between diethyl ether (2×400 mL) and water (2×300 mL). Organic layers were washed with brine (300 mL), combined, dried (MgSO4), filtered, and concentrated. Residue was recrystallized from hexanes to give 3-hydroxy-4-methyl-benzoic acid ethyl ester as white crystals in two crops. (Yield 29.14 g, 96.8%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1C=CC(C(C)C)=C[CH:17]=1>>[CH:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:17])[CH3:11]
Reactant: Cc1ccc(C(C)C)cc1
Reactant: c1ccc2ccccc2c1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out as in Example 7, but by reacting naphthalene with p-cymene. Yield of isopropylnaphthalene obtained was 51% with 93% β- and 7% α-isomer.
Reaction SMILES: [CH2:1]([C@H:8]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]([OH:25])[CH2:10][NH:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:38][C:39]1[O:43][N:42]=[C:41]([C:44]2[S:45][CH:46]=[C:47]([CH:49]=O)[N:48]=2)[CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]([OH:25])[CH2:10][N:11]([CH2:49][C:47]1[N:48]=[C:44]([C:41]2[CH:40]=[C:39]([CH3:38])[O:43][N:42]=2)[S:45][CH:46]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: Cc1cc(-c2nc(C=O)cs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NN(Cc1csc(-c2cc(C)on2)n1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A solution of Example 19A (0.4 g, 0.86 mmol) in dichloroethane (5.7 mL) was treated with acetic acid (99 μL, 2 equivalents), 2-(5-methyl-3-isoxazolyl)thiazole 4-carboxaldehyde (0.199 g, 1.2 equivalents), and sodium triacetoxyborohydride (0.545 g, 3 equivalents) and stirred at 25° C. for 16 hrs. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated. The crude residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 0.55 g (60%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1

Procedure:
2-(4-Fluorophenyl)-1-[4-(methylthio)phenyl]ethanone from Example 1, Step 1 (17.2 g, 66 mmol) was stirred with 15 mL dimethylformamide dimethylacetal in 80 mL dry DMF at 120° C. for 24 hours under nitrogen. The reaction mixture was cooled, diluted with two volumes of ethyl acetate, and the solution washed successively with water and brine and dried over Na2SO4. The solvent was removed under high vacuum and the resulting brown oil (23.9 g) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:12])[C:9]([NH2:11])=[S:10])[CH2:4][CH2:3]1.[ClH:13].[CH3:14][I:15]>CO>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:12])[C:9](=[NH:11])[S:10][CH3:14])[CH2:4][CH2:3]1.[ClH:13].[IH:15]
Reactant: CI
Reactant: CN(C(N)=S)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CO
Product: CSC(=N)N(C)[C@H]1CC[C@H](N)CC1
Product: I

Procedure:
A mixture of 0.6 g of 1-(trans-4-aminocyclohexyl)-1-methyl-thiourea in the form of a hydrochloride in 30 ml of MeOH and 0.22 ml of methyliodide is refluxed for 2 hours, solvent is evaporated and 1-(trans-4-aminocyclohexyl)-1,2-dimethyl-isothiourea in the form of a hydrochloride and a hydroiodide is obtained.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11](I)[CH:12]=1)[C:7]([OH:9])=[O:8]>O>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([OH:1])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a solution of NaOH (12.2 g; 305.8 mmol) in 300 mL of water was added 3-bromo-5-iodo-benzoic acid (20 g, 61.2 mmol) and Cu2O (866 mg, 6.1 mmol). The reaction mixture was heated at 100° C. for 24 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through Celite™. The filtrate was then acidified with 10% aq. HCl and extracted into ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a tan solid (12.3 g, 93% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:22][O:21][C:19]([C:14]1[C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=[CH:16][N:15]=1)=[O:20]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (30.0 g, 138 mmol) and methyl 3-aminopyrazine-2-carboxylate (21.2 g, 138 mmol) in DMF (200 mL) was heated at about 80° C. for about 16 h. The mixture was allowed to cool to ambient temperature and was neutralized with saturated aqueous NaHCO3. The mixture was diluted with DCM. The layers were separated and the aqueous layer was washed with DCM. The combined organic layers were washed with brine, dried over MgSO4, and eluted through a silica gel plug with EtOAc as the eluent. The combined organic layers were concentrated under reduced pressure to yield 30 g black oil. The material was diluted with DCM and the insoluble materials were removed by filtration to yield 2.0 g of the title compound. A second crop was obtained similarly to yield 1.8 g. The remaining filtrate was purified by flash silica gel chromatography using EtOAc as an eluent to yield an additional 3.1 g of the title compound (6.9 g, 15%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 272.3 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:19]([NH2:22])[CH2:20][OH:21].CCN(C(C)C)C(C)C>CCCCO>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]2[N:8]=[CH:3][N:4]=[C:5]([NH:22][CH2:19][CH2:20][OH:21])[CH:6]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)n2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 200 °C
Yield: 94 %

Procedure:
74 mg of chloro-N-(4-nitrophenyl)pyrimidin-4-amine hydrochloride, 23 mg of 2-ethanolamine and 84 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH=10:1. Pure 2-(6-(4-nitrophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]([O:7][CH2:8][CH2:9][NH:10][C:15]1[N:17]=[C:18]([Cl:19])[N:11]=[C:12]([Cl:13])[N:14]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(=O)OCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To 194 g of 33% 2-aminoethyl methacrylate hydrochloride solution in water being stirred at 0°-5° C. was added 1 l of additional water followed by dropwise addition of a solution of 74 g (0.4 mole) of cyanuric chloride in 400 ml of acetone. To this mixture was added 67.2 g (0.8 mole) of sodium bicarbonate in portions over a 1 hr. period. The mixture was then stirred for an additional hour at room temperature. The reaction was again cooled to 0°-5° C. and the product was collected by filtration and dried in vacuo at room temperature to give 84.6 g. Recrystallization from a solution of 600 ml of benzene and 850 ml of ligroin with carbon decoloration yielded 56.6 g (mp 138°-140° C.).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[C:28]1[C:36]2N=[N:34][NH:33][C:32]=2C=CC=1.Cl.[CH2:38](N=C=NCCCN(C)C)C.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C(NN)C(C)C.CN1CCOCC1>Cl.C(OC)(C)(C)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:34][NH:33][CH2:32][CH:36]([CH3:28])[CH3:38])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: Oc1cccc2[nH]nnc12
Agent: CC(C)CNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: COC(C)(C)C
Product: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
A solution of 4.05 kg of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 12 l of dimethylformanide was cooled to 4° C., treated with 1.97 kg of hydroxybenzotriazole hydrate and 2.466 kg of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride and stirred for 2 hours at 4° C. 3.895 kg of isobutylhydrazine ditosylate salt were added followed by 2.36 l of N-methyl-morpholine. The mixture was stirred for 2 hours at 4° C. and for 50 hours at room temperature, diluted with 12 l of 2M hydrochloric acid and 12 l of methyl tert.butyl ether and the organic layer was separated. The organic phase was washed with water, saturated sodium hydrogen carbonate solution and water and then evaporated to give a dark cream colored solid. Recrystallization from hexane gave 2.47 kg of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a cream colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19]OC(=O)C4C=CC=CC=4)[C:11]3=[O:29])[CH2:9]2)=[CH:4][CH:3]=1.[OH2:30].[OH-:31].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][C:3]4[CH:4]=[C:5]([CH:6]=[CH:7][CH:2]=4)[C:8]([OH:31])=[O:30])[C:11]3=[O:29])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O
Reactant: O=C(OCN1C(=O)C2(CC2c2ccc(Cl)cc2)c2ccccc21)c1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(1R,2S) and (1S,2R)-methyl-3-(((2-(4-chlorophenyl)-2′-oxospiro[cyclo-propane-1,3′-indoline]-1′-yl)methyl)benzoate (48 mg) was dissolved in 1 mL of methanol; then 0.1 mL of water was added followed by lithium hydroxide (10 mg). The mixture was stirred for 14 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL of DMF and purified by preparative HPLC to give the title compound as white powder (10 mg). LC/MS m/e calcd. for C24H18ClNO3: 403, observed (M+H)+: 404.1 1H NMR (400 MHz, DMSO-d6) δppm 2.12 (dd, J=9.09, 4.80 Hz, 1H) 2.40 (dd, J=7.96, 4.93 Hz, 1H) 3.19-3.24 (m, 1 H) 5.10 (s, 2H) 6.17 (d, J=7.33 Hz, 1H) 6.72 (t, J=7.58 Hz, 1H) 6.95 (d, J=7.83 Hz, 1H) 7.08 (t, J=7.83 Hz, 1H) 7.30-7.41 (m, 4H) 7.50 (t, J=7.71 Hz, 1H) 7.60 (d, J=7.58 Hz, 1H) 7.82-7.89 (m, 2 H) 13.04 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:14]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.[OH2:19]>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[CH2:3][CH2:4][C:5]([CH3:17])([CH3:16])[C:6]2[N:7]=[C:8]3[C:13]([CH2:12][CH2:11][CH2:10][C:9]3=[O:19])=[N:14][C:15]1=2
Reactant: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3
Reactant: O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
8.0 g of 1,2,3,4,6,7,8,9-octahydro-1,1,4,4-tetramethylphenazine was dissolved in 30 ml of acetic acid, followed by the dropwise addition of a solution of 4.9 g of chromic acid anhydride in acetic acid (30 ml)/water (4 ml). The obtained mixture was stirred at 80° C. for 30 minutes, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 20% ethyl acetate/hexane) to give 1.6 g of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]2[C:11](=[O:12])[O:10][C@H:9]([C@@H:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:8]2)=[CH:4][CH:3]=1.[OH-:31].[Na+].Cl.N1C=CN=C1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCOCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([CH2:8][C@H:9]([O:31][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@@H:13]([NH:21][C:22]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:28])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:10])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(Br)cc2)C(=O)O1
Agent: Cl
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](CC(Cc1ccc(Br)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution containing the product from Example 92B (18.4 g) in dioxane (190 mL) was treated with sodium hydroxide solution (45 mL, 1N) for 1 hour at 25° C. The mixture was cooled to 0° C., and acidified to pH 5 using 4N HCl, and concentrated under reduced pressure. The concentrate was partitioned between chloroform and water. The organic phase layer was washed with brine, dried over MgSO4, and concentrated. A solution of the residue (22 g) in dioxane (115 mL) was treated with imidazole (19 g, 279 mmol) and t-butyldimethylsilyl chloride (35 g, 232 mmol), stirred at 25° C. for 18 hours and concentrated. The residue was combined with ice, acidified with 4N HCl to pH 3, and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. A solution of the residue in a mixture of THF (180 mL), acetic acid (180 mL), and water (60 mL) was stirred for 1 hour at 25° C. and concentrated. The residue was chromatographed on silica gel eluting with 0-50% ethyl acetate in chloroform to give the title compound (14.18 g, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:23])[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:27](OC)([N:29](C)C)[CH3:28].[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:23])[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:34][NH:29][C:27]([CH3:28])=[C:10]2[N:9]=1
Reactant: NN
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)Oc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(F)c(OC(C)C)cc3N=C2NN1

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVh) was prepared by reacting 0.00198 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-(1-methylethoxy)-2H-1,4-benzodiazepin-2-thione (IIh) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=385.