Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][CH:2]=1>[Pd].C(O)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc2c1oc1ccccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1Nc1cccc2c1oc1ccccc12
Reaction time: 8 h

Procedure:
10% palladium on carbon (10%; 0.50 g, 0.47 mmol) was added to a Parr hydrogenation bottle. The bottle was purged with nitrogen. Next, N-(dibenzo[b,d]furan-4-yl)-3-nitropyridin-2-amine (3.8 g, 12.45 mmol) and 200 mL ethanol were added. The reaction mixture was hydrogenated overnight using a Parr hydrogenator. The reaction mixture was filtered through Celite® and the Celite® washed with dichloromethane and ethyl acetate. The filtrate was evaporated leaving a dark brown solid, which was not purified (3.32 g, 97%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(=[O:11])[CH3:10]>N1C=CC=CC=1.Cl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:11])[CH3:10]
Reactant: Nc1ccccc1I
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Iodoaniline (1.00 g, 4.56 mmol) was dissolved in pyridine (5 mL) and cooled to 0° C. After acetyl chloride (314 μL, 5.94 mmol) was added, the reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction was diluted with 1 N HCl and extracted with ether. The organic layer was dried (MgSO4) and concentrated to give the desired acetamide (assumed quantitative), which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c[nH]c1=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc([N+](=O)[O-])c[nH]c1=O)c1ccccc1

Procedure:
A solution of 100 mg. of 3-amino-5-nitro-2-pyridone in 1.5 ml. of pyridine was cooled and treated with 200 mg. of benzoyl chloride. After 2 hours water was added. The oil that separated was washed with water and triturated with ether. The resultant solid was recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone, m.p. 267°-268° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)(=O)OCC)C.[CH3:20][C:21]([CH3:23])=O.O>O1CCCC1>[CH3:20][C:21]([CH3:23])=[CH:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]#[N:19]
Reactant: CC(C)=O
Reactant: CCOP(=O)(Cc1cccc(C#N)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1cccc(C#N)c1
Temperature: 25 °C
Yield: 28 %

Procedure:
Sodium hydride (0.40 g, 10 mmol, 60% in oil) was suspended in tetrahydrofuran (5 mL), (3-cyanobenzyl)phosphonic acid diethyl ester obtained in Preparation Example 135 (2.53 g, 10 mmol) was added dropwise under stirring at room temperature. After stirring for 1 hour at 60° C., the solution was allowed to room temperature, acetone (0.92 g, 20 mmol) was added dropwise, and the solution was further stirred for 30 minutes at room temperature. Water (100 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with water, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3), and the title compound (0.44 g, 2.80 mmol, 28%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CC(C)[C@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (S)-2-amino-3-methylbutan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=461.3 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5](=[N:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)[O:6][CH2:7][CH3:8])=[N+]=[N-]>[Ni].C(O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:10]2[N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][N:1]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH:20]=1
Reactant: CCOC(CN=[N+]=[N-])=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a solution of 0.35 part of 2-(2-azido-1-ethoxyethylideneamino)-5-chlorobenzophenone produced in Step (2) in 10 parts by volume of ethanol is added 2 parts by volume of Raney nickel washed sufficiently with ethanol. The mixture is refluxed for 25 minutes and filtered to remove the Raney nickel. The filtrate is evaporated under reduced pressure and 7-chloro-2-ethoxy-5-phenyl-3H-1,4-benzodiazepine is obtained as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:17]2[N:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[CH:21]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:17]2[N:18]=[N:19][N:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Reaction time: 48 h
Yield: 74.2 %

Procedure:
5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (20 mg; 0.04 mmol; 1.0 eq.) was dissolved in MeOH (3 mL) and Pd/C (moistened, 50% water; 100 mg) was added. The reaction mixture was hydrogenenated at RT for two days in a Parr instrument (35 bars). Reaction mixture was filtered through a celite pad and dried under vacuum to give the title compound as a beige solid (14 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.25-8.09 (m, 3H), 7.73-7.62 (m, 2H), 7.64-7.49 (m, 1H), 7.40-7.29 (m, 1H), 3.81-3.39 (m, 8H), 2.98-2.56 (m, 4H), 2.22 (s, 3H), 2.06-1.66 (m, 5H). HPLC (Condition A): Rt 3.86 min (purity 87.8%). MS (ESI+): 472.3, MS (ESI−): 470.2.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[CH3:20][NH:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][N:23]=1.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:28][C:25]2[CH:24]=[N:23][C:22]([NH:21][CH3:20])=[N:27][CH:26]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: CNc1ncc(C=O)cn1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncc(CNc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 9.72 mg, 0.04 mmol) and 2-methylamino-pyrimidine-5-carbaldehyde (138, 11.0 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=378.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)o3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described starting from 150 mg (0.44 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-5-yl]piperidine and 96 μl (0.67 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:67])(=O)=O)CCCCCCCCCCCCCCC>>[I:67][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)Oc1ccon1

Procedure:
3-(3-Chloropropylsulfonylamino)-2-(3-isoxazolyloxy)-1-octadecylcarbamoyloxypropane III j2 is allowed to react and worked up by the same procedure as described in (5). m.p. 69°-71.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:26])([CH3:25])[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([OH:22])[C:14]2([CH3:24])[CH3:23])[CH:11]=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[C:1]([SiH2:5][O:6][C:7]([CH3:26])([CH3:25])[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]2([CH3:24])[CH3:23])[CH:11]=[N:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2ccccc2C(O)C1(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2ccccc2C(=O)C1(C)C
Temperature: 100 °C

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-2,2-dimethyl-indan-1-ol (372 mg, 1.0 mmol) in 1,4-dioxane is added manganese(IV) oxide (1.74 g, 20 mmol). The reaction is then heated at 100° C. for one hour, cooled to room temperature, filtered, and concentrated to afford 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-2,2-dimethyl-indan-1-one without the need for further purification; MS: (ESI) m/z 371.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=O)[N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:5]1[C:6]([CH3:8])=[N:7][C:3]([CH3:2])=[N:4]1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1nc(C)n(CC(=O)O)n1
Agent: Cl
Product: Cc1nc(C)n(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 27 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 256, (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (219 mg, 27%). 1H-NMR (400 MHz, CDCl3): σ 8.38 (s, 1H), 7.40-7.16 (m, 7H), 7.05-6.92 (m, 5H), 4.74 (s, 2H), 4.70-4.64 (m, 3H), 4.55 (d, 1H), 4.02-3.97 (m, 1H), 3.62-3.56 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H). MS (EI) for C28H28FN5O4. found 518.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:31](O)=[O:32])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH2:35][C@@H:36]([CH2:45][CH2:46][CH3:47])[C@H:37]([OH:44])[C:38]([NH:40][CH:41]1[CH2:43][CH2:42]1)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:31]([NH:35][C@@H:36]([CH2:45][CH2:46][CH3:47])[C:37](=[O:44])[C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[O:32])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=687.17 [M+H+].
Reaction SMILES: [ClH:1].Cl.CN(C)C(C1C=CC2C=C(C3C(C)=CN=C(NCCC4CCN(C)CC4)N=3)SC=2C=1)=O.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]3[CH:46]=[C:47]([C:50]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:51])[CH:48]=[CH:49][C:43]=3[CH:42]=2)[C:38]([CH3:58])=[CH:37][N:36]=1.C(O[C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][CH2:73][CH2:74][NH2:75])[CH2:68][CH2:67]1)=O)(C)(C)C>>[ClH:34].[ClH:1].[CH3:58][C:38]1[C:39]([C:41]2[S:45][C:44]3[CH:46]=[C:47]([C:50]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:51])[CH:48]=[CH:49][C:43]=3[CH:42]=2)=[N:40][C:35]([NH:75][CH2:74][CH2:73][CH2:72][CH:69]2[CH2:68][CH2:67][N:66]([CH3:64])[CH2:71][CH2:70]2)=[N:36][CH:37]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid dimethylamide di-hydrochloride, the title compound is synthesized from [2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophen-6-yl]-morpholin-4-ylmethanone and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as yellow foam. ES+(m/z) 494 [M(free base)+H].
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])=[O:6])[CH3:4].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28]([NH:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:10][CH3:11])[O:12][CH3:13])=[O:6])[CH3:4])=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COP(=O)(CNC(=O)[C@H](C)N)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)OC
Reaction time: 8 h

Procedure:
24.65 g of dimethyl (L-alanylamino)-methylphosphonate hydrochloride and 32.0 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine were stirred in 200 ml of dry dimethylformamide while 14 ml of dry triethylamine were added dropwise at 20° C. The mixture was stirred overnight and then the triethylamine hydrochloride filtered off and washed with a small amount of dimethylformamide. The filtrate was evaporated under an oil-pump vacuum, the residue treated with 150 ml of water and then extracted with four 125 ml portions of chloroform. The combined chloroform layers were washed with a 20 % potassium carbonate solution, separated and dried over sodium sulphate. The sodium sulphate was filtered off, the filtrate evaporated firstly under a water-pump vacuum and then under an oil-pump vacuum and the residue taken up in 100 ml of ethyl acetate. About 100 ml of ether were added to faint turbidity when crystallization began. After refrigeration overnight, the solid was filtered off, washed successively with ethyl acetate/ether (1:1) and ether and then dried in vacuo. Recrystallization from 200 ml of boiling ethyl acetate by the addition of 200 ml of ether gave 27.8 g of dimethyl [(N-benzyloxycarbonyl-L-alanyl-L-alanyl)amino] -methylphosphonate of melting point 106°-108° C; [α]D20 =- 37.4° (c =1% in glacial acetic acid).
Reaction SMILES: [CH3:1][SH-:2][C:3](=[S:9])[N:4]([CH2:7][CH3:8])[CH2:5][CH3:6].I([O-])(=O)(=O)=[O:11].[Na+].O>CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:6][CH2:5][N:4]([C:3]([S:2]([CH3:1])=[O:11])=[S:9])[CH2:7][CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)C(=S)[SH-]C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=S)S(C)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
S-Methyl-N,N-diethyldithiocarbamate sulfoxide (DDTC-Me SO) was prepared from S-Methyl-N,N-diethyldithiocarbamate (DDTC-Me). The synthesis of DDTC-Me was carried out as described by M. D. Faiman et al., Alcoholism, 7, 307 (1983). Sodium metaperiodate (200 mg) (Sigma Chemical Co.) was dissolved in 25 ml of 50:50 MeOH:H2O at 0° C. DDTC-Me (200 mg) was separately dissolved in 2 ml of methanol, and was then cooled to 0° C. before addition to a constantly stirring solution of sodium metaperiodate in MeOH:H2O. The reaction mixture was stirred for 24 hr at 0° C. and then was diluted to 100 ml with cold 0.1M potassium phosphate buffer (pH 7.4). The resulting colorless solution was then extracted with methylene chloride The organic layer was treated with activated charcoal, and the charcoal was removed by filtration through a Celite bed. The solvent was removed under reduced pressure to obtain the crude product which was then purified by preparative HPLC (C-18, 5 micron, 150 mm×10 mm column, Alltech) using 30:70 acetonitrile:H2O (acetonitrile, Fisher Scientific, HPLC grade) at a flow rate of 2.5 ml/min. The fractions containing the DDTC-Me SO were pooled and diluted with four times the original volume with water. The diluted pooled fractions were extracted with methylene chloride. The solvent was dried with sodium sulfate and removed under reduced pressure to yield 50 mg of product a colorless oil; 1H NMR (300 MHz, CDCl3) 3.25-3.42 (m, 4H), 2.72 (s, 3H), 1.23 (t, 3H), 1.17 (t, 3 H); mass spectoscopy: CIMS (NH3) M/Z, 180 (M+1); IR (neat): 2954, 1668, 1436, 1400, 1317, 1136, 1113, 747 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:12][CH:11]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2].C([Li])CCC.C(OC1C=CC=C(F)C=1F)C.CN(C)CCN(C)C.C([C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1)CC.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:28])[C:6]=3[F:27])=[CH:11][CH:12]=2)[CH2:19][CH2:20]1)[CH2:25][CH3:26]
Reactant: CCC[C@H]1CC[C@H](CCC2CC=C(c3ccc(OCC)c(F)c3F)CC2)CC1
Agent: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Agent: CCOc1cccc(F)c1F
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(OCC)c(F)c3F)cc2)CC1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
0.2 mol of 1-(4-ethoxy-2,3-difluorophenyl)-4-(trans-4-n-propylcyclohexylethyl)-cyclohex-1-ene (obtainable as follows: 131 ml of a 1.6N solution of butyllithium in n-hexane are added dropwise to a solution of 0.2 mol of ethoxy-2,3-difluorobenzene and 0.2 mol of tetramethylethylenediamine in 400 ml of tetrahydrofuran at -70° C., with exclusion of moisture and under a nitrogen atmosphere. The mixture is then stirred at -70° C. for 4 hours and 0.11 mol of 4-(trans-4-n-propylcyclohexylethyl)-cyclohexanone in 100 ml of THF are subsequently slowly added. The reaction mixture is allowed to warm slowly to room temperature and is hydrolysed with 1.5 l of a saturated ammonium chloride solution. The mixture is extracted with ether and the ether phase is washed several times with water, dried and evaporated. The residue is taken up in 700 ml of ethanol, 70 ml of concentrated HCl are added and the mixture is boiled under reflux for 3 hours. 1.5 l of water are then added and the mixture is extracted with methyl tert.-butyl ether. The ether phase is washed neutral, dried and evaporated and the residue is recrystallized. The product (has a mp. of 73° and a cp. of 139°) and 50 g of DDQ are boiled under reflux in 250 ml of toluene for one hour. After cooling, the reaction mixture is filtered with toluene over silica gel, the filtrate is evaporated and the residue is purified by chromatography. 1-(trans-4-Propylcyclohexyl)-2-(4'-ethoxy-2',3'-difluorobiphenyl-4-yl)-ethane is obtained, C 64° N 144° I.