Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:41]4[CH2:42][CH2:43][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=590.99 (M+H+); retention time=1.04 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8](Cl)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][CH2:8][N:1]1[CH:5]=[N:4][N:3]=[N:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1nnn[nH]1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCn2cnnn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
To a mixture of tetrazole (500 mg, 7.13 mmol) in 14 mL DMF at 0° C. was added NaH (60%, 286 mg, 7.13 mmol). The mixture was stirred at 0° C. for 20 min, then was treated with BOM-Cl (80%, 1.35 mL, 7.84 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 483 mg of Intermediate 12.1 as a colorless oil.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]=O.O1CCCC1.[CH3:15][NH:16][CH3:17]>O1CCCOC1>[CH3:15][N:16]([CH2:8][C:2](=[CH2:1])[C:3]([OH:5])=[O:4])[CH3:17]
Reactant: C=O
Reactant: CNC
Reactant: O=C(O)CC(=O)O
Agent: C1COCOC1
Solvent: C1CCOC1
Product: C=C(CN(C)C)C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
1 g of malonic acid and 0.63 g of paraformaldehyde were diluted with 10 ml of 1,3-dioxane, and 4.8 ml of a 2.0M dimethylamine-containing tetrahydrofuran solution was added thereto. The resulting mixture was heated to 70° C. and stirred for one hour. After the reaction terminated, the resulting solution was distilled under a reduced pressure. The resulting residue was crystallized with acetone and filtered under a reduced pressure to obtain the title compound (0.4 g, 32%) in the form of white crystal.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl.O1CCOCC1>[Pd].CO>[CH3:2][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccnc1-c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccnc1-c1cccnc1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A 3-hydroxymethyl-2,3′-bipyridyl (42.3 mg, 0.227 mmole) solution containing methanol (5 ml) and 4N solution of hydrogen chloride in dry 1,4-dioxane (0.57 ml, 2.3 mmole) was hydrogenated in the presence of palladium on activated carbon catalyst (10%, 40 mg) at room temperature and ambient pressure for 3 hours. The catalyst was filtered off, washed with methanol (3×1 ml), and the combined methanolic solutions were evaporated under vacuum. The residue was dissolved in water (2 ml), sodium carbonate was added (0.1 g) and the solution was extracted with dichloromethane (3×2 ml). The combined dichloromethane solutions were dried (magnesium sulfate) and rotary evaporated at 2 mm Hg-45° C., giving the pure product (29.4 mg, 76%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=[CH:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([O:18][C:19]2[N:24]=[CH:23][C:22]3[N:25]=[C:26]([C:30]4[C:31]([NH2:35])=[N:32][O:33][N:34]=4)[N:27]([CH2:28][CH3:29])[C:21]=3[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.O>N1C=CC=CC=1>[NH2:35][C:31]1[C:30]([C:26]2[N:27]([CH2:28][CH3:29])[C:21]3[CH:20]=[C:19]([O:18][C:14]4[CH:13]=[C:12]([NH:11][C:8]([C:5]5[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=5)=[O:9])[CH:17]=[CH:16][CH:15]=4)[N:24]=[CH:23][C:22]=3[N:25]=2)=[N:34][O:33][N:32]=1
Reactant: O=C(Cl)c1ccc(=O)[nH]c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
The product of Step 1 (93 mg, 0.6 mmol) was added to a solution of the product of Example 3 (200 mg, 0.6 mmol) in pyridine (1 mL) and the resulting mixture was allowed to stir at rt for 30 min. The solution was poured into H2O and the precipitate which formed as filtered, washed with H2O and Et2O and dried to give the title compound as a tan solid (150 mg, 55%). MS (ES+) m/e 459 [M+H]+.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[C:8]([Cl:18])=[C:9]([Cl:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.[ClH:19]>O>[Cl:19][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[Cl:18]
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1Cl
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A solution of sodium nitrate (39 g.) in water (85 ml.) is added over 1 hour to a solution of 5-amino-3,4-dichloro-α,α,α-trifluorotoluene (117.5 g., 0.51 mol) in 1700 ml. concentrated hydrochloric acid at -6° C. and the solution stirred for 1 hour then filtered. The filtrate is added to a solution of cuprous chloride (76.5 g.) in concentrated hydrochloric acid (500 ml.) over 5 minutes at 0° to 8° C. and gradually heated to 80° C. over 80 minutes. The reaction mixture is cooled to 35° C. and extracted with hexane (2×300 ml.). The extract is washed with water, 2% sodium hydroxide solution, dried and distilled to give 3,4,5-trichloro-α,α,α-trifluorotoluene (70 g., 55%) b.p. 82°-86° C./10 mm, 95% pure.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[F:1][C:2]1[CH:31]=[C:30]([CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:18]=3)[S:13][C:6]=12)[NH2:32]
Reactant: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cn2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cn2)CC1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a solution of 152 (150 mg, 0.311 mmol) in MeOH (20 mL) was added ammonium chloride (33.3 mg, 0.622 mmol) in water (5 mL) and zinc powder (81 mg, 3.01 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 153 (132 mg, 92% yield) that was used directly in the next step with no additional purification. MS (m/z)=453.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:38])[CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:38])[CH2:33][CH2:34][NH:35][C:36]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:37])[CH3:30]
Reactant: CCOC(=O)CCN=C=O
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Product: CCOC(=O)CCNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 84.7 %

Procedure:
In a manner similar to the method described in Example 49, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (100 mg, 0.236 mmol) was reacted with 3-isocyanato-propionic acid ethyl ester (168 mg, 1.174 mmol) to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid ethyl ester (113.2 mg, 85%). HRMS (ES+) m/z Calcd for C28H31Cl2F2N3O3+H [(M+H)+]: 566.1784; Found: 566.1785.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CS(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)NC(=O)C1(c2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (5.0 g, 20.7 mmol) was dissolved in toluene (30 mL) then thionyl chloride (17.7 mL, 243 mmol) was carefully added. The reaction was heated to reflux for 4 hours then concentrated and azeotroped with toluene (2×30 mL). The intermediate acid chloride was dissolved in toluene (50 mL) then methanesulfonamide (11.41 g, 120 mmol) and triethylamine (15 mL, 0.108 mmol) were added. The reaction was refluxed for 3 hours then cooled and submitted to standard aqueous workup. The crude material was purified on silica gel
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C@@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN[C@H]2c2ccccc2)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 19.6 %

Procedure:
A solution of 0.33 g (0.77 mmole) of 4-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (from Example 44, Step B) and 0.22 g (1.54 mmole) of 1-chloroethyl chloroformate in 4.5 mL of 1,2-dichloroethane was placed in a pressure vial which was lowered into an oil bath which was heated to 110° C. After stirring for 60 hr the solution was cooled and concentrated in vacuo. The residue was dissolved in 7 mL of methanol and the resulting solution was heated at reflux for 30 min. The mixture was cooled and treated with several drops of concentrated aqueous ammonia and the solution was concentrated. The residue was partly purified by flash chromatography on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride:methanol, and the rich cuts were purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g (20%) of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=O.[CH:25]([N:28](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN.C1COCC1>CN(C=O)C.CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([NH:28][CH3:25])=[O:21]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(F)c3)n12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(F)c1
Reaction time: 0.01 h

Procedure:
To a solution of 6-(3-fluorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.050 g, 0.15 mmol, from Step 3) in DMF (3 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.18 g, 0.49 mmol, Aldrich). After the reaction was stirred for 30 seconds, 2.0 M Methylamine in THF (0.62 mL, 1.2 mmol, Aldrich) was added. After 1 hour, the reaction was diluted with MeCN and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (35 mg, 67%).
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a cooled (0° C.) solution of 0.230 g (0.80 mmol) of the product of Step D dissolved in 4 mL of CH2Cl2 was added 0.263 g (1.00 mmol) of carbon tetrabromide and 0.333 g (1.00 mmol) of triphenylphosphine. After 15 minutes at 0° C., the reaction mixture was allowed to warm to room temperature and was stirred for an additional 6 hours. The reaction was then concentrated in vacuo and purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 097 g (35%) of the title compound.
Reaction SMILES: [CH2:1]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12])[CH2:2][CH2:3][C:4]#[CH:5].[CH2:23](O)[CH2:24][CH2:25][C:26]#[CH:27].C([NH:31]CC)C>ClCCl.[Cu]I>[N:31]1[CH:27]=[CH:26][CH:25]=[C:24]([C:5]#[C:4][CH2:3][CH2:2][CH2:1][C:6]2([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[S:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:23]=1
Reactant: CCNCC
Reactant: C#CCCCC1(S(=O)(=O)c2ccc(C)cc2)SC(=O)NC1=O
Reactant: C#CCCCO
Agent: [Cu]I
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)C2(CCCC#Cc3cccnc3)SC(=O)NC2=O)cc1

Procedure:
A solution of 5-pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione(1.0 mmol), 4-pentyn-1-ol (1.0 mmol), bistriphenylphosphine(Pd II) chloride (0.20 mmol), and copper(I) iodide (0.10 mmol) in 50 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the product was purified by chromatography to give the title compound as a light beige solid, mp 173-176° C., THEORY: C, 57.95, H, 4.38 N, 6.76. FOUND: C, 57.68, H, 4.35, N, 6.70.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([F:15])[C:10]([NH2:12])=[CH:11][C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2]
Reactant: [H][H]
Reactant: CCN1c2cc(F)c([N+](=O)[O-])cc2CS1(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN1c2cc(F)c(N)cc2CS1(=O)=O
Yield: 0.1 %

Procedure:
1-Ethyl-6-fluoro-1,3-dihydro-5-nitro-2,1-benzisothiazole 2,2-dioxide (Compound B from Example 1, Step C, 1.0 g), was suspended in tetrahydrofuran (20 mL) with 10% palladium on carbon (100 mg). The suspension was placed in Parr® shaker and treated with 50 psi (3.45×105Pa) of hydrogen overnight. The catalyst was then filtered off through diatomaceous earth (Celite®), and the filtrate was evaporated under reduced pressure to give the title compound of Step A as a brown solid (0.510 mg). 1H NMR (CDCl3): δ 6.92 (dd,1H), 6.04 (dd,1H), 4.08 (s,2H), 3.80 (br s,2H), 3.64 (q,2H), 1.32 (t,3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])[CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:14]1([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][S:27](=[O:30])[CH2:26][CH2:25]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4cccc5ccccc45)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4cccc5ccccc45)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(1-naphthylmethyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 212°-215° C.) and piperazine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]1([N:15]2[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=[C:11]2[C@@H:8]([NH2:7])[CH2:9][CH3:10])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(S)-1-(1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tertbutyl ester (1.76 g) in DCM (10 mL) was added TFA (7.5 mL) and the mixture was stirred at RT for 4 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM and washed with a saturated solution of NaHCO3. The two phase system was stirred for 20 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(1-Phenyl-1H-benzoimidazol-2-yl)propylamine as a brown oil (1.1 g, 81% over three steps). LCMS: RT 2.02 min [M+H]+ 252.2
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:9]1[N:14]=[C:13]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[N:12]=[C:11]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:18][C:17]2([CH3:29])[CH3:28])[N:10]=1
Reactant: CC(C)NC(C)C
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(c1nc(Cl)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1)C(C)C
Reaction time: 24 h

Procedure:
26.1 g (258 mmol) of diisopropylamine are added with stirring to a solution of 29.9 g (86 mmol) of the product from Example 17 in 100 ml of toluene. The mixture is heated to reflux and kept at this temperature for 24 hours. After cooling, a solution of 4.1 g of NaOH in 21 ml of water is added. The solid product is filtered off and recrystallized from 25 ml of toluene. A yellowish powder which melts at 179°-184° is obtained.
Reaction SMILES: [ClH:1].C(N(CC)CC)C.[Cl:9][C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][CH2:13][C:14]([CH3:27])=[CH:15][CH2:16][CH2:17][C:18]([CH3:26])=[CH:19][CH2:20][CH2:21][C:22](=[CH2:25])[CH:23]=[CH2:24].[ClH:30].[Cl-:31].[NH4+]>C(O)(=O)C.C(Cl)Cl>[Cl:1][CH2:24][CH:23]=[C:22]([CH3:25])[CH2:21][CH2:20][CH2:19][C:18]([Cl:31])([CH3:26])[CH2:17][CH2:16][CH2:15][C:14]([Cl:30])([CH3:27])[CH2:13][CH2:12][CH2:11][C:10]([Cl:9])([CH3:29])[CH3:28]
Reactant: Cl
Reactant: C=CC(=C)CCC=C(C)CCC=C(C)CCCC(C)(C)Cl
Reactant: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Temperature: -10 °C
Yield: 96.5 %

Procedure:
Triethylamine hydrochloride (0.48 g), methylene chloride (15 cc), acetic acid (10 cc) and cuprous chloride (90 mg) are introduced, under an argon atmosphere, into a 250 cc reactor. The reaction mixture is stirred until a homogeneous solution is obtained. This is cooled to -10° C. and 15-chloro-3-methylene-7,11,15-trimethyl-hexadeca-1,6,10-triene (10 g) is then added followed, over the course of 1 hour, by dry gaseous hydrogen chloride (3.9 g). The reaction mixture is poured into an aqueous solution (100 cc) of ammonium chloride (100 g/liter). The organic phase is removed by decanting and the aqueous phase is then extracted with methylene chloride (twice 100 cc). The combined organic phases are washed with water (100 cc) and then dried over potassium carbonate. After filtration and evaporation of the solvent, 1,7,11,15-tetrachloro-3,7,11,15-tetramethyl-hexadec-2-ene (13.1 g) is obtained in a yield of 96.5%.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2COc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]oxepin-11-yloxy)-ethanol (256 mg, 1.0 mmol), tributylphosphine (223 mg, 1.1 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (278 mg, 1.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 175 mg (37%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.93 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 3.65-3.75 (m, 1H),3.78-3.88 (m, 1H), 3.95 (t, 1H), 4.10 (t, 2H), 4.15 (q, 2H), 4.85 (d, 1H), 5.25 (s, 1H), 6.15 (d, 1H), 6.75 (d,2H), 6.85-6.95 (m, 2H), 7.10 (d, 2H), 7.15-7.40 (m, 6H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:28][CH:27]=1)[CH3:30]
Reactant: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 28.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-ethylphenethyl)-1-piperidinecarboxamide formate (0.60 g, 1.3 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.55 g, 1.3 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.295 g, 0.369 mmol).