Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Li].Cl[CH2:18][O:19][CH2:20][CH2:21][Cl:22]>O1CCCC1>[Cl:22][CH2:21][CH2:20][O:19][CH2:18][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1CCOCC1
Reactant: ClCCOCCl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC1(COCCCl)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carbonitrile (3.80 g, 34.2 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min to a cold (−78° C.) solution of lithium diisopropylamine (37.5 mmol) in tetrahydrofuran (50 ml). After 30 min, a solution of 2-chloroethyl chloromethyl ether (5.00 g, 38.7 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min and the mixture stirred for 30 min. The cooling bath was then removed and the solution was allowed to warm up to 25° C. then stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic fraction was dried over anhydrous magnesium sulfate and concentrated. Filtration of the residue on silica gel (elution toluene-ethyl acetate 8:2) followed by distillation in vacuo gave 6.33 g (91% yield) of the title nitrile as a clear oil: bp 90-100° C./0.2 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.74 (2H, m, CH2), 1.92 (2H, m, CH2), 3.58 (2H, s, CH2), 3.67 (2H, t, J=5.6 Hz, CH2), 3.74 (2H, dt, J=2.3 Hz and J=12.4 Hz, CH2), 3.83 (2H, t, J=5.6 Hz, CH2), 4.0 (2H, m, OCH2).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=2)[NH:25]1)[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:37])[CH:30]=2)[NH:25]1)[CH3:11]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of 60% sodium hydride (356 mg, 8.9 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (1 g, 8.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A47. A solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.27 mmol) and 1,1′-carbonyldiimidazole (412 mg, 2.54 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B47. Solution B47 was added to Solution A47 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (100 mg, 15%) as a white solid: MS (ESI) M+1=498.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][C:8]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccccc2)c2ccc(O)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
(E)-1-(3-Hydroxyphenyl)-3-phenylprop-2-en-1-one (48.7 g, 217 mmol) obtained in Step 1 and CF3COOH (161 mL, 10 eq) were placed into a flask and stirred for 24 h at 80° C. After cooling to room temperature, toluene (200 mL) was added and the solution was concentrated to remove TFA under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated in vacuo to obtain the desired product (48.0 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[C:6]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:46](Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:31]([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[C:7]2[C:8](=[O:10])[NH:9][C:46](=[O:48])[NH:1][C:2]=2[N:3]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc3[nH]c(=O)[nH]c(=O)c23)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylate (0.400 g, 0.800 mmol), which was obtained in the step (1) of Example 7-1, in THF (10 mL) were added triethylamine (0.50 mL, 3.58 mmol) followed by triphosgene (0.354 g, 1.19 mmol). The reaction mixture was stirred at room temperature for 12 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1) and recrystallized from ethanol to give tert-butyl 3-{7-[2-(benzyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl}-1-piperidinecarboxylate as a white solid. (0.406 g, yield; 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[O:33]=[C:32]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2)[CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: CC(C)(C)OC(=O)Cn1ccc2cc(NC(=O)CC34CC5CC(CC(C5)C3)C4)ccc21
Yield: 60.4 %

Procedure:
Prepared according to the method of Example 15b) from 5-nitro-1H-indole-1-acetic acid, 1,1-dimethylethyl ester (0.29 g) and 1-adamantaneacetyl chloride (0.20 g) to give the title compound as a white solid (0.24 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=1.[F-].[Cs+].[CH:13]1([CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:13]1(/[CH:18]=[C:19](\[C:2]2[S:3][CH:4]=[C:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(C(=CC2CCCC2)CO)OC1(C)C
Reactant: CS(=O)(=O)c1csc(Br)c1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1csc(/C(=C\C2CCCC2)CO)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Add 2-bromo-4-methanesulfonyl-thiophene (241 mg, 1.0 mmol), caesium fluoride ( 304 mg, 2.0 mmol) and tetrakis-(triphenylphosphin)-palladium(0) (58 mg, 0.05 mmol) to a solution of 3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (252 mg, 1.0 mmol) in THF. Stir at 50° C. for 24 h, monitore completion of the reaction by LCMS. Treat the reaction mixture with water and extract with ethyl acetate. Dry organic layers over sodium sulfate and remove solvents under vacuum to obtain 405 mg crude product. Purify by silica gel chromatography, eluting with gradient from 9:1 to 1:1 hexane:ethyl acetate to obtain 118 mg purified product. MS (m/e): 309.0 (M+Na).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:20])[CH2:12][CH2:11][CH2:10][NH:9][C:8]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=2.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[CH3:5][C:6]1([CH3:20])[CH2:12][CH2:11][CH2:10][N:9]([C:1](=[O:3])[CH3:2])[C:8]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=2
Reactant: CC(=O)Cl
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCC(C)(C)c2ccc([N+](=O)[O-])cc21
Yield: 73.4 %

Procedure:
Acetyl chloride (0.77 mL, 11 mmol) was added to a suspension of crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g, 5.45 mmol) and NaHCO3 (1.37 g, 16.3 mmol) in CH2Cl2 (20 mL). The mixture was heated at reflux for 1 h. After cooling, the mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 64% over two steps).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[C:30]([CH2:32][CH2:33][NH2:34])#[N:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[C:30]([CH2:32][CH2:33][NH:34][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23])#[N:31]
Reactant: N#CCCN
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NCCC#N)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (40 mg) was treated with cyanoethylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (29 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:17]1([C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCCC2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(C1CCCCC1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclohexanecarbonylpiperidin-4-one (89.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclohexylmethanone (116 mg, 63%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=10.18 min, m/z 429.46 (36), 427.44 (M++H, 100). HPLC tr=4.43 min (93.94%) 1H NMR (270 MHz, CDCl3) δ 1.12-1.79 (15H, m, 7CH2+NH), 2.44 (1H, m, CHCO), 2.64 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.80 (2H, m, CH2NH), 3.82 (1H, m, ½CH2), 4.39 (1H, br d, J=13.3 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.22 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.3, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 25.97, 29.40, 29.59, 32.29, 33.40, 40.32 (CH2), 40.54 (CH), 43.91, 45.65 (CH2), 54.00 (CH), 118.94, 119.61, 124.54, 127.96, 128.70, 129.84, 130.57, 131.84, 154.35, 156.38 (ArC), and 174.48 (C═O).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[N:8]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C@H:7]([CH2:26][CH3:27])[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[N:8]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@H:7]([CH2:26][CH3:27])[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(O)cc2)c2cc(F)ccc21
Yield: 94 %

Procedure:
(3R)-1-Butyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1-butyl-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (94%). [α]D25=−268° (c=0.0103G/ML, CHCl3); MS (ESI) m/z 371 ([M+H]+); MS (ESI) m/z 369 ([M−H]−); HRMS: calcd for C21H23FN2O3, 370.1693; found (ESI_FT), 371.17594; Anal. Calcd for C21H23FN2O3: C, 68.09; H, 6.26; N, 7.56. Found: C, 67.96; H, 6.60; N, 7.67.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:44])[N:15]=1)=[O:13])[CH3:2].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:44])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)OC(C)(C)C)cc3OC)nc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl}amino)-3-methoxybenzoate (0.450 g, 0.75 mmol) in DCM (6 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:19](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To 2,6-dichloro-4-nitrobenzoic acid (12.8 g, U.S. Pat. No. 3,423,475) was added anhydrous CH2Cl2 (60 mL) and thionyl chloride (40 mL) then the resulting mixture was refluxed for 19 h. The mixture was allowed to cool to room temperature and evaporated. Additional CH2Cl2 (10 mL) was added and the solution was evaporated. MeOH (100 mL) was added to the residue and the mixture was refluxed for 17 h. The mixture was allowed to cool to room temperature and placed in an ice-bath. The precipitated solid was collected by filtration to give methyl 2,6-dichloro-4-nitrobenzoate (10.8 g, 80%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:36]=[CH:35][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=3)=[C:17]([Cl:18])[C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:18][C:17]1[C:13]2[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH:36]=[CH:35][C:14]=2[S:15][C:16]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:21]([C:31]([F:33])([F:32])[F:34])[CH:20]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
3-{[3-Chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester (43 mg, 0.079 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 23 mg of 3-{[3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.10 (s, 1H), 7.96-8.02 (m, 3H), 7.54 (d, 1H), 7.46 (d, 1H), 7.35-7.37 (m, 3H), 7.28-7.29 (m, 2H), 4.37 (s, 2H), 3.26 (m, 2H), 2.71 (m, 2H), MS (ES+) 490.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].BrC1C(=O)C(Br)=C(Br)C(C)([N+:30]([O-:32])=[O:31])C=1Br>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[C:14]([N+:30]([O-:32])=[O:31])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c([N+](=O)[O-])c1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (243 mg, 0.845 mmol) in trifluoroacetic acid (1.7 mL) was treated with 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadien-1-one (396 mg, 0.845 mmol). The resulting mixture was placed under a N2 atmosphere, sonicated briefly, and stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (50 mL), washed successively with water, 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a brown oil (659 mg). The crude product was purified by flash chromatography on a Biotage 40S KP-Sil column, eluting with 10:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to an orange gum (113 mg, 40%) which was lyophilized from benzene to provide 7-amino-9a-butyl-6-fluoro-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].Cl>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Yield: 77 %

Procedure:
Condensation of BocGlyOPFP (7.2 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 10.2 g.) by the actived ester method gave BocGly-Leu-MetNH2 in 73% yield. De-t-butoxycarbonylation of BocGly-Leu-MetNH2 (9.38 g.) using hydrogen chloride in acetic acid gave HGly-Leu-MetNH2 in 77% yield. Condensation of BocD, LBpaOH (1.6 g.) and H-Gly-Leu-MetNH2 (2.13 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocD,LBpa-Gly-Leu-MetNH2, de-t-butoxycarbonylation of which (1.1 g.) using hydrogen chloride in acetic acid gave HD, LBpa-Gly-Leu-MetNH2 in 30% overall yield.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:20][O:21][C:22](=[O:36])[C:23]1[CH:28]=[C:27]([NH2:29])[C:26]([NH2:30])=[N:25][C:24]=1[O:31][CH2:32][CH:33]([F:35])[F:34].C(Cl)CCl>CC#N.O>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:29][C:27]3[C:26]([N:30]=2)=[N:25][C:24]([O:31][CH2:32][CH:33]([F:35])[F:34])=[C:23]([C:22]([O:21][CH3:20])=[O:36])[CH:28]=3)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cc(N)c(N)nc1OCC(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Solvent: CC#N
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2[nH]c(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)nc2nc1OCC(F)F
Reaction time: 2.5 h

Procedure:
A mixture of N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (4.00 g, 12.6 mmol) and 5,6-diamino-2-(2,2-difluoro-ethoxy)-nicotinic acid methyl ester (3.10 g, 12.5 mmol, prepared according to WO2010/034799) in MeCN (30 ml) is stirred for 2.5 h, then EDC (2.75 g, 14.3 mmol) is added and it is stirred at reflux for 15 min. The mixture is diluted with water, concentrated and extracted with DCM. The organic phase is dried with MgSO4, filtered and concentrated.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.C([O-])(=[O:17])C.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[O:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:17])[NH:3][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccc(Oc2ccccc2)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(Oc2ccccc2)n[nH]1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
A mixture of 3-chloro-6-phenoxy-pyridazine (1.01 g, 4.89 mmol) and sodium acetate (1.40 g, 17.06 mmol) in glacial acetic acid (50 mL, 0.1M) was heated to 110° C. overnight. After this time the reaction was cooled to 25° C. and was diluted with water (450 mL). The reaction was brought to pH=5-6 by the addition of a 5N aqueous sodium hydroxide solution. The resulting solution was extracted with ethyl acetate (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The resulting oil was azeotroped with methanol four times and dried in vacuo to afford 6-phenoxy-2H-pyridazin-3-one (0.78 g, 86%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 7.00 (d, J=10.0 Hz, 1H), 7.13-7.27 (m, 3H), 7.34-7.46 (m, 3H), 12.29 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from (4-hydroxy-phenyl)-phenyl-methanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (36%, colorless oil). HPLC-MS: m/z=332.2 (M+1); Rt: 4.42 min.