Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-methyl benzenesulfonyl chloride (251 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12e as a solid (275 mg, 82%). HPLC: 99.62% (Rt=9.22 min).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N ethyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) dropwise and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (48 mg, 49%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.99 (s, 3H), 1.21 (t, J=7.03 Hz, 3H), 1.31-1.54 (m, 6H), 1.58-2.00 (m, 9H), 2.06-2.35 (m, 3H), 2.88-3.04 (m, 2H), 3.04-3.18 (m, 2H), 3.29-3.44 (m, 2H), 3.48-3.69 (m, 3H), 4.08 (q, J=7.03 Hz, 2H). MS (M+1): 393.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([F:16])[F:15])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([F:15])[F:16])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(OCC(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
To a solution of methyl 2-chloro-5-(2,2-difluoroethoxy)benzoate (55 mg) in MeOH (1 mL) was added 1M aqueous lithium hydroxide (0.88 mL), and the solution was stirred at room temperature for 12 hours. The reaction mixture was stirred under ice-cooling, 2M hydrochloric acid was added slowly to acidify to pH 2-3, and the precipitated solid was filtered. The solid was washed sequentially with a small amount of water and diethyl ether, and dried under reduced pressure to obtain the titled compound (28 mg) as white powder.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]([OH:32])=O.[C:33]1([C:39]2[N:40]=[C:41]3[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][N:42]3[CH:48]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:33]1([C:39]2[N:40]=[C:41]3[CH:46]=[C:45]([NH:47][C:30]([C:25]4[N:26]([CH3:29])[N:27]=[CH:28][C:24]=4[Cl:23])=[O:32])[CH:44]=[CH:43][N:42]3[CH:48]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
Under an atmosphere of nitrogen, N—N-diisopropylethylamine (749 mg, 6 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 744 mg, 1.94 mmol) were added to a solution of 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (310 mg, 1.94 mmol, Art-Chem B000148) in DMF (5 ml). After 30 min, 2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (404 mg, 1.94 mmol) was added, and the brown solution was stirred over the weekend (r.t.). The reaction mixture was taken up in ethyl acetate and washed with water. After drying (Na2SO4), the solvent was evaporated and the title compound (170 mg, 25%) was isolated by column chromatography (silica gel, heptane:ethyl acetate=100:0-50:50). MS (m/e)=352.2 [M+H+].
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[NH:10][C:11](=[O:19])[C:12]([C:17]#[N:18])=[C:13]([S:15][CH3:16])[N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>COCCOC>[C:17]([C:12]1[C:11](=[O:19])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:14][C:13]=1[S:15][CH3:16])#[N:18]
Reactant: CSc1nc(C2CCCCC2)[nH]c(=O)c1C#N
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cn1c(C2CCCCC2)nc(SC)c(C#N)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a cooled (0° C.), stirred suspension of NaH (50% dispersion in mineral oil, washed with hexane, 2.2 g, 0.047 mol) in DME (350 mL) was added 2-cyclohexyl-1,6-dihydro-4-(methylthio)-6-oxo-5-pyrimidinecarbonitrile (9.5 g, 0.038 mol) in several portions. After 1 hour, methyl bromoacetate was added and the resulting solution was heated at 95°-100° C. for 2 days. The solution was cooled and water (300 mL) was added. The mixture was extracted with ethyl acetate and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a beige powder (12.2 g, 99%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:16]C(=O)OC(C)(C)C)[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-5) (3.7 g, 9.63 mmol) in TFA (20 mL) was stirred at room temperature for 1 hour. The mixture was poured into a sat. NaHCO3 solution, extracted with CHCl3, dried (Na2SO4), filtered, and concentrated under reduced pressure to give 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octan-2-amine (7-1).
Reaction SMILES: [ClH:1].CCOCC.[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[CH2:18][S:17](=[O:37])(=[O:36])[C:16]2[CH:38]=[CH:39][CH:40]=[CH:41][C:15]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[CH2:18][S:17](=[O:37])(=[O:36])[C:16]2[CH:38]=[CH:39][CH:40]=[CH:41][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](C(=O)NC1CS(=O)(=O)c2ccccc2N(Cc2ccccc2)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)NC1CS(=O)(=O)c2ccccc2N(Cc2ccccc2)C1=O
Reaction time: 3 h
Yield: 100 %

Procedure:
1 M HCl in Et2O (4 mL, 4.00 mmol, Eq: 40) was added to a solution of tert-butyl (S)-1-(5-benzyl-1,1,4-trioxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate in MeOH (1.5 mL). After 3 h, the mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (45 mg, 100%). MS m/z 402.0 (MH+)
Reaction SMILES: Br.C([O:4][P:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([P:22]([O:27]CC)(=[O:26])[O:23]CC)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])[O:6]CC)C.O>C(O)(=O)C>[C:16]1([C:13]2[CH:14]=[CH:15][C:10]([P:5]([OH:6])(=[O:4])[OH:9])=[CH:11][CH:12]=2)[CH:17]=[CH:18][C:19]([P:22]([OH:26])(=[O:23])[OH:27])=[CH:20][CH:21]=1
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(P(=O)(OCC)OCC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=P(O)(O)c1ccc(-c2ccc(P(=O)(O)O)cc2)cc1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
66 ml of HBr at 33% by weight in acetic acid are added to 4.9 g (11.5 moles) of 4,4'-biphenyl-diphosphonic acid tetra-ethyl ester and the mixture is heated at 80° C. for 4 hours. After cooling to ambient temperature, 150 ml of H2O are added under agitation and the precipitate obtained is filtered, washed with water and vacuum dried (20 mm Hg) at 45° C. for one night. 2.29 g of 4,4'-biphenyl-diphosphonic acid, with a molar yield of 66% are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-morpholin-4-yl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B1) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as an amorphous red substance (1.72 g).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[S:9][C:8]([S:10](NN)(=[O:12])=[O:11])=[CH:7][CH:6]=1.[Br:15]Br>CCCCCC>[Cl:4][C:5]1[S:9][C:8]([S:10]([Br:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NNS(=O)(=O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClCCl
Product: O=S(=O)(Br)c1ccc(Cl)s1
Temperature: 2 °C
Yield: 50.2 %

Procedure:
In a 1-liter, three-neck flask equipped with a magnetic stirrer, a thermometer, an an addition funnel were placed 300 ml of methylene chloride, 10.63 g (0.05 mol) of 5-chloro-2-thiophenesulfonyl hydrazine, and some crushed ice. The slurry was allowed to cool to 2° C., and 16.0 g (0.10 mol) of bromine was added dropwise with stirring at such a rate that the temperature did not exceed 10° C. After the addition was complete, the methylene chloride layer was separated, dried and the methylene chloride removed in vacuo, leaving a yellow-orange oil. The oil was dissolved in hexane and the resulting solution cooled to give 6.56 g of the title compound as slightly yellow crystals, mp 35°-37°.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH2:30][NH2:31])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH2:30][C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:21][N:20]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ncc1OCCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (120 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (130 mg, 0.48 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine hydrochloride (130 mg, 0.48 mmol, Amine-58) in a similar manner to Intermediate-2.
Reaction SMILES: NC1N=NC(N)=NN=1.Cl.NN=C(N)N(N)N.CC(=O)CC(=O)C.[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]2[NH:32][NH:33][C:34]([N:37]3[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[N:38]3)=[N:35][N:36]=2)[N:26]=1.[N]=O.[N+]([O-])=O>O>[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]2[N:32]=[N:33][C:34]([N:37]3[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[N:38]3)=[N:35][N:36]=2)[N:26]=1
Reactant: Cc1cc(C)n(C2=NN=C(n3nc(C)cc3C)NN2)n1
Agent: Cl
Agent: NN=C(N)N(N)N
Agent: Nc1nnc(N)nn1
Solvent: CC(=O)CC(C)=O
Solvent: O
Product: Cc1cc(C)n(-c2nnc(-n3nc(C)cc3C)nn2)n1

Procedure:
This invention is a method of making 3,6-diamino-1,2,4,5,-tetrazine (compound 5, DATZ). Triaminoguanidine monohydrochloride (compound 1) in water solution is combined with 2,4-pentanedione (compound 2) to form a precipitate comprised of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2-dihydro-1,2,4,5-tetrazine (compound 3). A mixture of compound 3 in a suitable solvent is contacted with nitric oxide (NO) or nitrogen dioxide (NO2) to form 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (compound 4). The NO or NO2 is then removed from the mixture by passing an inert gas through the mixture or, alternatively, compound 4 is separated from the mixture and mixed with fresh solvent to form a mixture free of NO and NO2. The mixture is contacted with ammonia (NH3), first at a temperature below about 35 C and then at a temperature above about 50 C, to form 3,6-diamino-1,2,4,5-tetrazine and 3,5-dimethyl-lH-pyrazole (compound 7). A preferred solvent is 1-methyl-2-pyrrolidinone (NMP).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.C([O:25][C:26](=[O:29])[CH2:27][NH2:28])C.[OH-].[K+].Cl>>[C:26]([CH2:27][NH:28][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([OH:29])=[O:25]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CNc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 75.5 %

Procedure:
A suspension of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.31 g 1.00 mmol) and glycine ethyl ester hydrochloride (0.69 g, 5.00 mmol) in a solution of 4M aqueous potassium hydroxide (3.8 mL, 15.0 mmol) was heated to 90° C. for 15 hours. The reaction mixture was cooled to room temperature and it was treated with 2M aqueous hydrochloric acid to adjust the pH to ˜5. It was partitioned with ethyl acetate (50 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the solvent gave 2-({4-[(carboxymethyl)amino]-3-nitrophenyl}carbonyl)benzoic acid (0.26 g, 76% yield) as a white residue. MS (EI) for C16H12N2O7: 342 (M−).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14]>CC(O)C.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: NCCOCCO
Reactant: O=C1NC(=S)CS1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C1N=C(NCCOCCO)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-thioxo-1,3-thiazolidin-2-one (10 g) in 2-propanol (25 mL) and ethyl acetate (75 mL) was added 2-(2-aminoethoxy)ethanol (7.50 mL), and the mixture was stirred at room temperature for 2 hr and further stirred for 2 hr under ice-cooling. The precipitate was collected by filtration, and the obtained solid was washed with ethyl acetate to give the title compound (12.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH2:9][NH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[O:16]=[C:17]1[CH2:22][O:21][C:20]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:19]=2[NH:18]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][N:10]([CH3:11])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]1[CH:25]=[N:26][C:19]2[NH:18][C:17](=[O:16])[CH2:22][O:21][C:20]=2[CH:23]=1
Reactant: CCCOc1c(CNC)cccc1OC
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)cccc1OC
Reaction time: 0.13 h
Yield: 35.5 %

Procedure:
To a solution of (3-methoxy-2-propoxyphenyl)-N-methylmethanamine (75 mg, 0.36 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (75 mg, 0.26 mmol), 1-hydroxybenzotriazole (50 mg, 0.36 mmol), diisopropylethylamine (150 uL, 0.67 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (72 mg, 0.36 mmol). The mixture was placed in a microwave at a temperature of 140° C. for 8 minutes. The product precipitated with the addition of water and was filtered, triturated with ether and dried to yield title compound as a white solid (38 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 8.03-8.12 (rotamers, 2s, 1H), 7.63-7.69 (dd, J=15.2 Hz, J=11.2 Hz, 1H), 7.44-7.35 (rotamers, 2s, 1H), 7.02-7.04 (m, 1H), 6.80-6.91 (m, 2H), 6.72 (d, J=7.2 Hz, 1H), 4.67-4.81 (rotamers, 4s, 4H), 3.91-4.01 (m, 2H), 3.90 (2s, rotomers, 3H), 3.10 (s, 3H), 1.76-1.89 (m, 2H), 1.05 (t, J=7.2 Hz, 3H); MS (ESI) m/e 412 (C22H25N3O5+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of trimethylsilylidazomethane in CH2Cl2 (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6-aminonicotinate as a yellow solid. Title compound was prepared from this crude methyl 6-aminocincotinate in 17% yield according to a procedure similar to that described in Preparation 6.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([S:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]2)(=[O:18])=[O:17])([CH3:15])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH3:4].[C:29]([Si:33](Cl)([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)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([Si:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[O:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([S:16]([CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][CH2:25]2)(=[O:18])=[O:17])([CH3:15])[CH3:14])[O:8][N:7]=1)([CH3:4])[CH3:5])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO)no2)CC1
Solvent: ClCCl
Product: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)no2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 116.1 %

Procedure:
To a solution of 0.41 g (0.96 mmol) of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in DCM (8 ml) are added imidazoles (0.07 g, 0.96 mmol), followed by tert-Butylchlorodiphenylsilane (0.26 g, 0.96 mmol). The reaction is stirred at room temperature for 20 h. The mixture is diluted with DCM (10 mL) and washed with saturated aqueous NH4Cl solution, brine, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to give 0.73 g of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide. Yield: 100%, ES-MS: 655 [M+H].
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:15]([NH:17][C@H:18]([CH2:29][OH:30])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:16])C1C=CC=CC=1>C(O)C.[Pd]>[C:35]([O:34][C:32]([NH:31][C@H:14]([C:15]([NH:17][C@H:18]([CH2:29][OH:30])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:16])[CH2:13][CH2:12][CH2:11][NH2:10])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)[C@H](CCCN)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 81A from 50 mg (0.09 mmol) of benzyl((4S)-4-[(tert-butoxycarbonyl)amino]-5-{[(1S)-3-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)propyl]amino}-5-oxopentyl)carbamate (Example 93A) in 50 ml of ethanol with the addition of 5 mg of palladium on activated carbon (10%). The product is reacted without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Sc3ccccc3)cc2c1O
Agent: I
Product: CCCCOC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O
Yield: 34 %

Procedure:
540 mg of 1-bromo-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1.25 mmol) were reacted with red phosphorous and HI analogously to Example D-1 f). The crude product was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 150 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.78 (s, 1H), 8.71 (d, 1H), 8.11 (t, 1H), 7.79 (d, 1H), 7.39 to 7.54 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH:8]([CH3:12])[CH2:7]2.[BH4-].[Na+].O.Cl>C1COCC1.CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:14])[CH3:15])[CH:5]=[C:6]2[C:10]=1[CH:9]=[C:8]([CH3:12])[CH2:7]2
Reactant: CC1Cc2cc(C(C)C)cc(Br)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC1=Cc2c(Br)cc(C(C)C)cc2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 22.2 g (83.2 mmol) of 7-bromo-5-isopropyl-2-methyl-1-indanone in 120 ml of THF-methanol (2:1, vol.), 5.06 g (133 mmol) of NaBH4 was added with vigorous stirring over 3 h at 0° C. This mixture was stirred overnight at room temperature; then, 300 ml of cold water was added, and the resulting mixture was acidified with 1 M HCl to pH 1. The organic layer was separated, and the aqueous layer was extracted with 3×150 ml of dichloromethane. The combined organic fractions were dried over K2CO3 and evaporated to dryness, and 200 ml of toluene was added to the yellowish oil obtained. This toluene solution was treated with a catalytic amount of pTolSO3H (ca. 0.2 g) for 1 h at reflux, cooled to room temperature, and evaporated to dryness. The crude product was purified using flash chromatography on Silica Gel 60 (40-63 μm, d 40 mm, l 400 mm; eluent: hexanes). Yield 19.6 g (94%) of 4-bromo-6-isopropyl-2-methyl-1H-indene.