Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[NH3:10].O>C1(C)C=CC=CC=1>[C:5](=[O:6])([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])[NH2:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>>[NH2:1][CH2:2][CH2:3][CH2:4][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Product: NCCCc1cc2ccccc2[nH]1

Procedure:
In step 1 of Scheme B, a 3-amino-propanol compound f is treated with trifluoroacetic anhydride to afford a trifluoroacetylated propyl compound g. In step 2, the trifluoroacetylated compound g, is then heated in the presence of indole h, and the resulting residue treated with base such as sodium hydroxide to provide a 3-aminopropyl indole compound i. Compound i is a compound of formula X in accordance with the invention, wherein R3 is hydrogen.
Reaction SMILES: C=O.[N:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:8][CH2:7][CH:6]([C:9]2[N:18]3[C:12]([CH2:13][NH:14][CH2:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=43)=[N:11][N:10]=2)[CH2:5][CH2:4]1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:29][N:14]1[CH2:13][C:12]2[N:18]([C:9]([CH:6]3[CH2:7][CH2:8][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:4][CH2:5]3)=[N:10][N:11]=2)[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(N2CCC(c3nnc4n3-c3ccccc3CNC4)CC2)nc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2ccccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
Formaldehyde (37% w/v aqueous, 1 ml, 81 mmol) was added to a solution of the amine of example 1 (100 mg, 0.28 mmol) in dichloromethane (20 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) was added. The reaction mixture was stirred for a further 0.25 hours. The dichloromethane was removed under reduced pressure. The residue was partitioned between 2N aqueous sodium hydroxide solution (50 ml) and ethyl acetate (50 ml). The organic layer was washed with saturated brine and dried over magnesium sulphate before filtering and evaporating the filtrate under reduced pressure to give the title compound as a pale yellow foam (75 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:23]=[C:24]([NH:28]C(=O)OC(C)(C)C)[S:25][C:26]=2[CH3:27])=[C:20]2[C:15]([N:16]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:17](=[O:38])[N:18]([CH3:37])[C:19]2=[O:36])=[N:14]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:28][C:24]1[S:25][C:26]([CH3:27])=[C:22]([C:21]2[N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[N:14]=[C:15]3[C:20]=2[C:19](=[O:36])[N:18]([CH3:37])[C:17](=[O:38])[N:16]3[CH2:39][CH:40]2[CH2:41][CH2:42]2)[N:23]=1
Reactant: Cc1sc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by treating tert-butyl 4-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-methyl-1,3-thiazol-2-ylcarbamate with 10% TFA in dichloromethane at room temperature for 5 hours. Mass: 508.13 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH:22]=4)[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:22]=4)[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(C2(c3ccc(-c4cnc(N)nc4)cc3)C=CC(=O)CC2)cc1OC1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C2(c3ccc(-c4cnc(N)nc4)cc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 87.3 %

Procedure:
A slurry of 4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cyclohexen-1-one (1.2 g, 2.63 mmol) in ethyl acetate (20 ml) with palladium on activated carbon (360 mg, 30% w/w) was stirred under hydrogen at atmospheric pressure for three days then filtered and the residue washed with dichloromethane. The combined organic solution was evaporated to afford the title compound as a gray solid (1.05 g, 88% crude yield). 1H-NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.44 (d, 2H, J=8.4), 7.38 (d, 2H, J=8.4), 6.89 (dd, 1H, J=8.4, J=2.2), 6.84 (d, 1H, J=8.4), 6.83 (d, 1H, J=2.2), 5.21 (s, 2H), 4.69 (m, 1H), 3.83(s, 3H), 2.64 (m, 4H), 2.48 (m, 4H). 1.81 (m, 6H), 1.57 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])(=[O:16])=[O:15].[C:27]([N:46]1[C:50]([CH2:51][C:52](O)=[O:53])=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[C:17]([S:14]([NH:13][CH2:12][CH2:11][C:3]2[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=2[NH:1][C:52](=[O:53])[CH2:51][C:50]2[N:46]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:47]=[N:48][N:49]=2)(=[O:16])=[O:15])[CH:22]=1)#[N:24]
Reactant: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1NC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
To a stirred solution of 0.30 g of N-[2-(2-amino-4-isopropylphenyl)ethyl]-5-cyano-2-methoxybezenesulfonamide, 0.298 g of (1-trityl-1H-tetrazol-5-yl)acetic acid and 0.129 g of 1-hydroxybenzotriazole monohydrate in 2.4 mL of N,N-dimethylformamide was added 0.140 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.549 g of N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-trityl-1H-tetrazol-5-yl)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][CH2:23]1)=[O:21])[CH3:18].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:40])[C@@H:29]([NH:39][C:14]([C:10]2[CH:11]=[C:12]([OH:13])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:9]=2)=[O:16])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(O)n(-c2cccc(F)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.500 g 1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (prepared by standard procedure using 3-fluorophenylhydrazine hydrochloride and sodium diethyl-2-oxosuccinate followed by ester hydrolysis) and 3.864 g 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF 1.723 g HOBt, 1.9 ml DIPEA and 2.157 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.332 g, 0.914 mmol) in THF (6 mL) and water (3 mL) was added LiOH (0.066 g, 2.74 mmol), and the solution immediately turned from yellow to orange-red. The reaction was stirred vigorously at room temperature for 16 h. The solution was acidified to pH 2 and diluted with water and CH2CI2. The phases were separated and the aqueous layer was extracted with EtOAC (3×10 mL) and the combined organic fractions were washed with water (10 mL), washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to give the title compound as a tan solid (0.29 g, 91%): mp 228-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.55-10.24 (m, 1H), 9.46 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.9 Hz, 4H), 7.64 (d, J=8.5 Hz, 2H); ESIMS m/z 350 ([M+H]+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:18][C:14]1[CH:13]=[C:12]([CH:11]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]2=[O:33])[CH2:10][CH2:9][OH:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(C(CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Reaction time: 1 h
Yield: 83.9 %

Procedure:
1′-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl) propyl]spiro-[cyclohexane-1,3′-indol]-2′(1′H)-one (0.85 g, 1.82 mmol) was dissolved in tetrahydrofuran and tetrabutyl ammonium fluoride (1.0 M in THF, 3.64 mL, 3.64 mmol) was added and the mixture was stirred for 1 hour. Reaction was quenched with saturated aqueous ammonium chloride then saturated sodium bicarbonate was added, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane) to afford 0.54 g (84%) racemic 1′-[1-(3-fluorophenyl)-3-hydroxypropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one that was resolved by chiral HPLC
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([F:25])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 4-fluoro-3-trifloromethyl aniline (0.077 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.043 g of desired product. 1H NMR (DMSO-d6): δ 7.46-7.59 (m, 3H), 7.69 (t, J=6.3 Hz, 1H), 8.11 (br s, 5H), 8.26 (m, 1H), 10.59 (br s, 1H), 12.72 (br s, 1H); MS (m/z): 495.07[M+H]+.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:19][CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O.[H-].[Na+].CI.[CH2:26]1COCC1.O>C1COCC1>[CH3:1][O:3][CH2:4][CH:5]([N:19]([CH3:26])[CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=CNC(CCOc1cccc2ccccc12)COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC(CCOc1cccc2ccccc12)N(C)C=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)-1-butanol formate, described in Example 3, in THF (30 ml) is added dropwise to a suspension of 51% sodium hydride (600 mg) in THF (30 ml). The mixture is heated at 40° C. for one and a half hours and then cooled to room temperature. A solution of methyl iodide (2.4 g) in THF (10 ml) is added and the mixture stirred at room temperature for 18 hours. Excess sodium hydride is decomposed by the addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated to dryness. The oily residue is subjected to chromatography on silica gel. Elution with methanol-chloroform (1:30) gives the title compound, nmr (CDCl3) δ 2.05 (m, 2H), 2.85 (s, 3H), 3.35 (s, 3H), 3.6 (m, 1H), 4.15 (m, 4H), 6.75-8.35 (7H), 8.15 (s, 1H).
Reaction SMILES: [C:1](OCC)(OCC)([O:3][CH2:4][CH3:5])[CH3:2].[C:12](#[N:16])[CH2:13][C:14]#[N:15].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH3:5])[CH3:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(C)=C(C#N)C#N
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Triethyl orthoacetate (1.6 L, 9 mol), malononitrile (500 g, 7.57 mol) and glacial acetic acid (25 ml) were placed in a 5 l RB flask equipped with a stirrer, thermometer and a Vigreux column (20×1 in.) on top of which a distillation condenser was placed. The reaction mixture was heated and ethyl alcohol began to distil when the temperature of the reaction mixture was about 85-90° C. After about 3 h., the temperature of the reaction mixture reached 140° C. Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was stirred with isopropyl alcohol (1 l) and cooled in an ice bath. The crystallized product was filtered off washed with isopropyl alcohol (200 ml), hexanes (600 ml) and dried at 50° C. in a vacuum oven overnight to yield 2-(1-ethoxy-ethylidene)-malononitrile (974 g, 94%) as a golden yellow solid [mp 92.° C. (lit.90-92° C., MCCall. M. A. J. Org. Chem. 1962, 27, 2433-2439.)].
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Cl:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Cl:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12
Reactant: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2oc3c(Cl)cc(-c4csc(C(C)C)n4)nc3c2c1Cl

Procedure:
The crude 10C (8.75 g, 23.34 mmol) was added to POCl3 (200 mL) The mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring. The yellow solids were collected by filtration and purified by flash chromatography to give product M10 (0.66 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][NH:2][CH2:3][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]1
Reactant: CNC(=O)[C@H](CC1CCC(C)CC1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNC[C@H](CC1CCC(C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of tert-butyl (S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)-ethylcarbamate (1.0075 g, 3.38 mmol, 1.0 equiv) in THF (40 mL) at 0° C. under N2 was added 1.0 M LiAlH4 in THF (7 mL, 7 mmol, 2.1 equiv). The mixture was stirred at rt for 19 h and sodium sulfate decahydrate (6.45 g, 20 mmol) was added carefully to quench excess LiAlH4. The mixture was filtered and the solid was washed with ether. After the solvents were removed in vacuo, the crude product (1.04 g) was used in the next step without further purification. LC-MS (3 min) tR=1.37 min, m/z 285 (MH+), 229.
Reaction SMILES: [CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15]C)=[CH:10][C:9]=1[CH3:17])\[CH3:7])[CH2:2][CH3:3].B(Br)(Br)Br>ClCCl.O>[CH2:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:17])\[CH3:7])[CH2:2][CH3:3]
Reactant: CCCO/N=C(\C)c1cc(C)c(OC)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCO/N=C(\C)c1cc(C)c(O)cc1C
Yield: 52 %

Procedure:
To a solution of 0.5 g (2.0 mmol) of (E)-1-(4-methoxy-2,5-dimethylphenyl)ethanone-propyloxime obtained in Step 4 in 15 mL of dichloromethane was added boron tribromide (BBr3) (0.28 mL, 2.9 mmol) and the reaction mixture was allowed to react at room temperature with stirring. After completion of the reaction, the residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.23 g of (E)-1-(4-hydroxy-2,5-dimethylphenyl)ethanone propyloxime as a white oil (yield: 49%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])[CH2:31][C:32](=[O:34])[OH:33])=[O:28])=[O:24])OCC[O:18]2)=[CH:13][CH:12]=1)(=[NH:10])[NH2:9]>FC(F)(F)C(O)=O.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36])[CH2:31][C:32](=[O:33])[OH:34])=[O:28])=[O:24])=[O:18])=[CH:13][CH:12]=1)(=[NH:9])[NH2:10]
Reactant: N=C(N)c1ccc(C2(CC(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc3ccccc3)C(=O)O)OCCO2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)CC(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A solution of 100 mg of N-[N-[N-[[2-(p-amidinophenyl)-1,3-dioxolan-2-yl]acetyl]glycyl]-L-α-aspartyl]-3-phenyl-L-alanine trifluoroacetate in 10 ml of trifluoroacetic acid/water 9:1 is left to stand at room temperature overnight. After removal of the solvent, chromatography of the residue (RP-18; elution with water-water/acetonitrile 1:1) and recrystallization there are obtained 33 mg of N-[N-[N-[(p-amidinobenzoyl)acetyl]glycyl]-L-aspartyl]-3-phenyl-L-alanine trifluoroacetate (1:1), m.p. 225°-230° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)([CH3:6])[CH2:3][CH2:4][OH:5]>C(O)(C(F)(F)F)=O>[CH3:6][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCO)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 214.3 %

Procedure:
A solution of 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The mixture was then concentrated in vacuo and the residue was stirred for 2 hours in a mixture of methanol (30 mL), ammonium hydroxide (30 mL), and ethylenediamine (8 mL). The mixture was then concentrated, and the residue was diluted with water and extracted with several portions of 15% IPA/CH2Cl2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 20 g of white solid. The solid was triturated with ether and the product was isolated by filtration to give the product as a white solid (7.75 g, 83%).
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:6]=1[NH:7]2.[CH3:19]I>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1C=CC=CC=1>[CH3:19][N:7]1[C:8]2[C:4](=[CH:3][CH:11]=[CH:10][CH:9]=2)[C:5]2[C:18]3[C:13]([CH2:12][C:6]1=2)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CI
Reactant: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cn1c2c(c3ccccc31)-c1ccccc1C2
Reaction time: 2 h
Yield: 78.2 %

Procedure:
In a 0.5 l bulb were placed 100 ml 50% aqueous NaOH, 100 ml benzene, 6.1 g (28 mmol)of 5,6-dihydroindeno[2,1-b]indole, prepared in Example 4, 1.8 ml (28 mmol) of MeI and 0.5 g of trimethylcetylammonium bromide. After having stirred the obtained mixture for 2 hours, the formation of an organic phase was observed; said phase was separated, washed twice with water (100 ml) and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from ethanol, obtaining 4.8 g of N-methyl-5,6-dihydroindeno[2,1-b]indole (yield=78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: CCO
Reactant: O=C(O)Cc1cc(Br)c(O)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Br)c(O)c(Br)c1

Procedure:
3,5-Dibromo-4-hydroxyphenylacetic acid (60 g, 0.19 mol), from Preparation A, was suspended in 1 L of ethanol and 10 mL of concentrated sulfuric acid and heated at reflux overnight. The reaction mixture was cooled, concentrated and the product collected by filtration, washed with water, and dried in a vacuum oven to obtain ethyl 3,5-dibromo-4-hydroxyphenylacetate.