Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH3:24])#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=2[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(C(=O)OCC)cc1C
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), ethyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (1) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Br:18][C:19]1[CH:23]=[C:22]([C:24]2[O:29][C:28](=[O:30])[C:27]3[CH:31]=[C:32]([Br:36])[CH:33]=[C:34]([Br:35])[C:26]=3[N:25]=2)[N:21]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:20]=1>O>[Br:18][C:19]1[CH:23]=[C:22]([C:24]([NH:25][C:26]2[C:34]([Br:35])=[CH:33][C:32]([Br:36])=[CH:31][C:27]=2[C:28]([N:4]([CH3:3])[NH:5][CH3:6])=[O:30])=[O:29])[N:21]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:20]=1
Reactant: CNNC
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNN(C)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.8 %

Procedure:
To a mixture of 0.42 g of N,N′-dimethylhydrazine dihydrochloride, five drops of water, 0.87 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.60 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 19 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.51 g of 3-bromo-N-[4,6-dibromo-2-(N,N′-dimethylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31]Br)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:37]([CH:40]([CH3:42])[CH3:41])CC)(C)C.C1(N)CC1.Cl>C(#N)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31][NH:37][CH:40]2[CH2:42][CH2:41]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CC#N
Product: O=C(CNC1CC1)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 305A (100 mg, 0.196 mmol) and diisopropylethylamine (0.034 mL, 0.19 mmol) in acetonitrile (1 mL) was added cyclopropanamine (11 mg, 0.19 mmol) and the reaction mixture was heated at about 60° C. for about 1 hour. The reaction mixture was cooled to ambient temperature and hydrochloric acid (4 N in dioxane, 1 mL) was added. The reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.28 (s, 1H), 8.56 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.30-7.45 (m, 5H), 5.64 (s, 2H), 3.45 (s, 2H), 2.18-2.26 (m, 1H), 1.89 (s, 3H), 0.37-0.45 (m, 2H), 0.29-0.37 (m, 2H). MS (ESI+) m/z 388 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.I[CH2:42][C:43]([NH2:45])=[O:44]>C(#N)C.CN(C)C=O>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)[CH2:42][C:43]([NH2:45])=[O:44])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNCCCCc2ccc(O)cc2)c1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN(CCCCc2ccc(O)cc2)CC(N)=O)c1
Temperature: 25 °C

Procedure:
To a solution of 4-[4-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]amino]butyl]phenol (15 mg in a mixture of 0.7 mL acetonitrile and 0.2 mL N,N-dimethylformamide) was added 0.015 mL of diisopropylethyl amine followed by 8 mg of iodoacetamide and the mixture stirred at room temperature. After 4.5 hours the crude reaction mixture was applied to a silica gel preparative TLC plate and eluted with (methylene chloride:methanol, 93:7). Isolation of the desired band was followed by extraction with methylene chloride:methanol (95:5) and further purification of this material by flash chromatography on silica gel (hexane:ethyl acetate, 2:5) to give the title compound (16 mg). m/e=470 (M+H)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:7]2.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:8]1[CH2:9][CH:10]2[CH2:13][CH2:14][CH:6]([CH2:12][CH2:11]2)[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C1CC2CCC1CNC2
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in 50 ml of ethyl ether was added with stirring to a cold mixture of 3-azabicyclo[3.2.2]nonane (6.26 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in 250 ml of ethyl ether. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 72 hours. The resulting white material was filtered and washed well with ethyl ether and ethyl acetate. The solvent was removed on a rotary evaporator and the residue taken u in ethyl ether, hexane added and the solution chilled. The remaining small amount of insoluble material was filtered and the solvent evaporated, leaving the product as an oil. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:9]#N)=[CH:5][CH:4]=1.[CH:23]([CH:25]=C)=O>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([N:7]2[CH:25]=[CH:23][CH:9]=[C:8]2[C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: C=CC=O
Reactant: COc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Product: COc1ccc(-n2cccc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methoxyanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a yellow powder (yield 9%), melting at 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:31][C:30]=1[Cl:29]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=585.9 [M+H+].
Reaction SMILES: O(C1C=CC(CCCCN)=CC=1)CCOCCOC.[O:20]([C:34]1[CH:39]=[CH:38][C:37]([CH:40](C(OCC2C=CC=CC=2)=O)[CH2:41][CH2:42][CH2:43][NH2:44])=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>>[O:20]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCCOCCOCCOc1ccc(C(CCCN)C(=O)OCc2ccccc2)cc1
Agent: COCCOCCOc1ccc(CCCCN)cc1
Product: COCCOCCOCCOCCOc1ccc(CCCCN)cc1
Yield: 95.9 %

Procedure:
This compound was prepared in a similar fashion to the synthesis of amine 107 from compound 110 (385 mg, 0.78 mmol) to give 266 mg (95%) of compound 111. 1H NMR (300 MHz, CDCl3) δ 1.41–1.54 (m, 2H), 1.60 (br s, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 3.37 (s, 3H), 3.51–3.58 (m, 2H), 3.60–3.77 (m, 10H), 3.84 (m, 2H), 4.10 (t, 5.5 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: OCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 6-bromo hexan-ol (F) (2 g, 11 mmol) in CH2Cl2 (50 ml) was added dropwise dihyrdopyran (1.6 ml, 16.5 mmol) followed by para-toluenesulphonic acid (commercially available) (0.075 g). The reaction mixture was stirred at room temperature for 16 h. The dark blue solution was then washed with water (2×25 ml) then saturated hydrogen carbonate solution (25 ml) and finally with a saturated sodium chloride solution (25 ml). The organic phase was then dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude material was then purified through flash silica gel chromatography (hexane/EtOAc, 10:1) to afford compound 2-(6-Bromo-hexyloxy)-tetrahydropyran (G) as an oil (0.5 g, 70%).
Reaction SMILES: [H-].[Na+].C(O)C.[CH3:6][C:7](=[O:10])[CH2:8][CH3:9].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O.S(=O)(=O)(O)O>>[O:14]=[C:12]([CH2:6][C:7](=[O:10])[CH2:8][CH3:9])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CC
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a suspension of sodium hydride (44 g, 1.10 mol, 60% in mineral oil) dry ethanol (318 mL, 5.44 mol) was added dropwise at a temperature of 0° C. Ten minutes after the addition was completed and still at 0° C., a mixture of 2-butanone (90 mL, 1.0 mol) and diethyl oxalate (136 mL, 1.0 mol) was added dropwise. The reaction mixture was stirred at rt over night. Then, sulfuric acid was added (4N aq., 550 mL, 1.1 mol). The crude product was extracted into diethyl ether. After washing with water and brine, the organic extract was dried over anhydrous magnesium sulfate, followed by filtration and evaporation of the solvent. The residue was subjected to distillation in vacuo. At a boiling point of 68-78° C. (2.2-2.6 mbar) the product was obtained as a colorless liquid (68.4 g, 40%): 1H NMR (400 MHz, CDCl3) δ 14.40 (broad, 1H), 6.38 (s, 1H), 4.36 (quart, 2H), 2.53 (quart, 2H), 1.38 (t, 3H), 1.17 (t, 3H); DCI(NH3)-MS m/z 173 (MH)+, 190 (M+NH4)+; HPLC RT (Method I) 4.02 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20](F)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.C(OC(=O)C1C=C(OCC)C([Cl:49])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([Cl:49])=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 505.2 (MH+).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:49][CH3:50])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:49][CH3:50])=[C:31]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[N:41]=4)[N:38]=3)[CH:48]=2)=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 73.2 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (40 mg, 0.21 mmol), oxalyl chloride (23 μL, 0.27 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (60 mg, 0.18 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (67 mg, 74%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:33][C:34]2[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[N:14]=2)=[N:10][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:20]12[NH:25][CH:23]([CH2:22][CH2:21]1)[CH2:24][CH:18]([C:15]1[N:14]=[C:13]([NH:12][C:9]3[N:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([O:2][CH3:1])=[O:41])=[CH:7][C:8]=3[O:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)[S:17][N:16]=1)[CH2:19]2
Reactant: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.7 %

Procedure:
tert-Butyl 3-(5-(5-(2-methoxy-2-oxoethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (461 mg, 0.770 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (5 mL) was added. The reaction was stirred at ambient temperature for 15 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford methyl 2-(6-(3-(8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (402 mg, 0.806 mmol, 105% yield) as a pale yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:57])[C@@H:9]([CH3:56])[C:10]([NH:12][C@H:13]([C:34]([N:36]1[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][CH2:45][CH2:44]2)[CH2:39][Si:38]([CH3:55])([CH3:54])[CH2:37]1)=[O:35])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O>[C:1]([O:5][C:6]([N:8]([CH3:57])[C@@H:9]([CH3:56])[C:10]([NH:12][C@H:13]([C:34]([N:36]1[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][CH2:45][CH2:44]2)[CH2:39][Si:38]([CH3:54])([CH3:55])[CH2:37]1)=[O:35])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1)C(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)N(C)C(=O)OC(C)(C)C
Yield: 89.5 %

Procedure:
A solution of methyl 4-((4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)phenyl)carbamoyl)benzoate (160 mg, 0.200 mmol) and LiOH (300 mg) in MeOH (6 mL) and H2O (2 mL) was stirred at rt for 2.5 h. Most of the MeOH was removed in vacuo and the residue was mixed with EtOAc and 1N HCl (60 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the title compound (140 mg, 0.179 mmol, 71% yield) as a white solid. MS(ESI+) m/z 784.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:18])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
200.0 mg (0.92 mmol) of trans-4-trifluoromethylcinnamic acid were treated with 200 μl of thionyl chloride. After addition of 2 drops of DMF, the reaction solution obtained was stirred at 75° C. for 3 h. It was then concentrated to dryness, and the residue was taken up in toluene 2× and concentrated to dryness again. Drying in a high vacuum yielded 237.0 mg of the title compound as a slightly yellow, amorphous powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([O:30]CC)=[O:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([OH:30])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1
Yield: 62.5 %

Procedure:
{1-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.669 g, 1.52 mmol), potassium hydroxide (0.30 g, 5.3 mmol) in THF (15 mL) and water (15 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 90° C. furnished the title compound as a light yellow solid (0.391 g, 63%), mp: 210-211° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 412; 1 HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.55-7.6 (m, 3H), 7.5 (dd, 2H, J=6.5 Hz and 1.8 Hz), 7.3-7.35 (m, 5H), 5.6 (s, 2H), and 1.3 ppm (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][CH2:25][CH:24]=[CH2:23])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-(benzyloxycarbonyl)-L-serine methyl ester (63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluroromethanesulfonic acid (5 mL, 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give N-(benzyloxycarbonyl)-O-2-propenyl-L-serine methyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)C(C)C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-(isobutyrylamino-methyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and isobutyryl chloride. MS calcd. for C22H22ClN2O4 [(M+H)+] 413.1, obsd. 413.0.
Reaction SMILES: [C:1](Cl)([Cl:3])=O.Cl.Cl.Cl.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:10]=1[O:16][CH2:17][CH:18]([OH:32])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:31]>O>[ClH:3].[N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:16][CH2:17][CH:18]([OH:32])[CH2:19][NH:20][CH2:21][CH2:22][NH:23][C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:31])[C:9]=2[NH:8][CH:1]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Agent: Cl
Solvent: O
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2nc[nH]c12

Procedure:
Phosgene is passed into a solution of 21.5 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 400 ml. water for 45 minutes, while cooling (internal temperature 20° to 25° C.). After flushing with nitrogen, the aqueous supernatant is decanted off and the precipitate recrystallized from ethanol/methanol (1:1 v/v), with the addition of active charcoal. There are obtained 6.6 g. (35% of theory) of the desired compound; m.p. 248°-250° C.