Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Cl)c1N
Temperature: 25 °C

Procedure:
3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2 °2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming ) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(Cc2cc(F)cc(C(F)(F)F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a solution of methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-4-carboxylate (4.10 g, 12.84 mmol) in DCM (50 mL) cooled in an ice-bath was added DIPEA (3.5 mL, 20.09 mmol) followed by methyl carbonochloridate (1.112 mL, 14.12 mmol). After completed addition the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the organic layer was washed with brine, then dried over MgSO4 and evaporated to yield crude dimethyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (4.94 g, 102%) as a pale yellow oil. MS m/z 378 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[F:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:19])[C:8](=[O:17])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][C:3]=1[F:24]
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
Ethyl 7-chloro-6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (580 mg, 1635 μmol) was dissolved in 1,4-dioxane (3270 μL) and N-ethyl-N-isopropylpropan-2-amine (854 μL, 4905 μmol). tert-Butyl 2-aminoacetate hydrochloride (411 mg, 2452 μmol) was added, and the reaction was stirred at 80° C. for 2 hours. The reaction was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title (30 mg) compound as a white solid after flash chromatography. MS m/e=440 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[C:8](\[CH3:14])/[CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH2:4][CH3:5])[CH3:2]>O1CCCC1>[CH2:1]([N:3](/[CH:6]=[CH:7]/[C@H:8]([CH3:14])[CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C/C=C(\C)C(OC)OC
Solvent: C1CCOC1
Product: CCN(/C=C/[C@H](C)C(OC)OC)CC
Temperature: 90 °C

Procedure:
A Pyrex bomb tube was charged with 2.02 g (10 mmol) of (E)-N,N-diethyl-4,4-dimethoxy-3-methyl-2-butenylamine, 10 ml of tetrahydrofuran and 83.2 mg (0.10 mmol) of [η4 -bicyclo[2.2.1]hepta-2,5-diene][(S)-(6,6'-dimethyl-2,2'-biphenylylene)-bis(diphenylphosphine)]rhodium (I) tetrafluoroborate. After degasifying the mixture, the tube was sealed and heated at 90° C. for 56 hours in a bomb tube oven. The red-brown solution was evaporated and the residue was distilled in a bulb-tube at about 70°/0.2 mmHg. There was obtained (1E,3S)-N,N-diethyl-4,4-dimethoxy-3-methyl-1-butenylamine; purity according to gas chromatography 70%; [α]D20 =-12.9° (c=4.05% in hexane). The corresponding (S)-4,4-dimethoxy-3-methylbutanal has a rotation [α]D20 =-23.3° (c=4.66% in hexane); purity according to gas chromatography 96%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[C:34]([CH3:36])[N+:33]([O-:37])=[C:32]([CH3:38])[CH:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[C:34]([CH3:36])[N+:33]([O-:37])=[C:32]([CH3:38])[CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.354, m/z=493; 1H NMR (CDCl3) 1.18 (d, 6H), 1.48 (d, 3H), 2.08-2.21 (m, 5H), 2.36 (m, 1H), 2.53 (s, 6H), 2.82 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.18 (m, 4H), 7.28 (m, 2H).
Reaction SMILES: B(Br)(Br)Br.ClCCl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23]C)=[C:13]([CH:22]=1)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([OH:23])=[C:13]([CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]=1
Reactant: COc1ccc(Cl)cc1C=Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)cc1C=Cc1ccccc1
Reaction time: 12 h
Yield: 49.4 %

Procedure:
Under argon atmosphere, 1 mol/L boron tribromide/dichloromethane solution (0.5 mL, 0.5 mmol) was added to a solution of 5-chloro-2-methoxy-β-phenylstyrene (80 mg, 0.3 mmol) in dichloromethane (2 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (15 mL), and after it was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (34.2 mg, 45.4%) as a white powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[S:15][C:16]([CH3:30])=[C:17]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]3)[N:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](O)=[O:38].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:30][C:16]1[S:15][C:14]([C:6]2[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=[C:4]([CH2:3][NH:2][C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[O:38])[CH:5]=2)=[N:18][C:17]=1[CH2:19][N:20]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(CN)cc(C(F)(F)F)c3)sc2C)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(CNC(=O)c4ccccn4)cc(C(F)(F)F)c3)sc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution (3 mL) of the compound (200 mg, 0.43 mmol) obtained in Example 95f in N,N-dimethylformamide were added 2-pyridinecarboxylic acid (64 mg, 0.52 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (80 mg, 0.52 mmol) and triethylamine (0.12 mL, 0.86 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=30/70) to give the title compound (79 mg, 35%) as a pale-orange oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([C:32]#[N:33])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][C:18]=1[C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: N#Cc1cccnc1-c1cc(B(O)O)ccc1F
Product: N#Cc1cccnc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 71 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (35 mg, 0.15 mmol) was coupled to 4-fluoro-3-(3-cyanopyridin-2-yl)phenylboronic acid (54 mg, 0.22 mmol) as described in Example 7 part g), affording 2-[2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl]nicotinonitrile (42 mg, 71%). δH (360 MHz, CDCl3) 7.44-7.57 (2H, m), 7.62-7.70 (2H, m), 7.75 (1H, dd, J 2.5 and 6.7), 7.87 (1H, d, J 8.8), 8.17 (1H, dd, J 1.8 and 7.7), 8.62 (1H, d, J 8.4), 8.95 (1H, dd, J 1.6 and 4.7), 9.29 (1H, d, J 4.6). m/z (ES+) 395 [MH]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:28])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][N:37]=[N:36][CH:35]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.CO.[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>[N:36]1[CH:35]=[CH:34][C:39]([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]3[C:10]([F:28])=[N:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)[CH:14]=3)[CH:3]=2)=[CH:38][N:37]=1
Reactant: Nc1cnc(Br)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cnc(-c2ccnnc2)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 110 °C

Procedure:
A mixture of 6′-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine (200 mg, 0.45 mmol), 4-(tributylstannyl)pyridazine (334 mg, 0.91 mmol) and lithium chloride (192 mg, 4.5 mmol) in 1,4-dioxane (5 mL) was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)-palladium(0) (39 mg, 0.034 mmol) was added and the reaction was heated at 110° C. for 24 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in DCM containing 0 1% ammonia) to afford a brown residue that was taken to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.O.[CH3:18][N:19]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Si:10]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 5-bromo-2-({[t-butyl(dimethyl)silyl]oxy}methyl)pyridine (0.30 g, 1.0 mmol) that was obtained in Example 23 (23a), zinc cyanide (0.18 g, 1.5 mmol), bis(dibenzylideneacetone)palladium (18 mg, 0.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol) in N-methyl-2-pyrrolidinone (4 ml) was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (0.23 g) in a yield of 93% as a white crystalline solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[C:10]([C:29]#[N:30])=[N:9][C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])=[C:17]4[OH:18])=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4c(c3)OCO4)ccc12

Procedure:
Prepared in analogy to example 31h from 6-(benzo[1,3]dioxol-5-yloxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 408 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(N(CC)CC)C>[Cl:14][C:5]1[C:4]2[CH2:3][CH2:2][N:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]=2[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[N:6]=1
Reactant: NC1CCCC1
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CCN(CC)CC
Product: Clc1nc2ccnn2c2c1CCN2C1CCCC1
Yield: 187.6 %

Procedure:
Synthesis was performed by the reaction of 11.0 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine with 1.80 g of cyclopentylamine and 8.87 g of triethylamine in accordance with the synthetic process in Example 54 to obtain 10.42 g (yield: 90.4%) of the intended product. White crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12]Cl)[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[OH-].[Na+].CN(C)C=O>[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: Oc1ccccc1
Reactant: CCOC(CCl)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccccc1)OCC

Procedure:
0.94 g (10 mmol) of phenol, 1.52 g (10 mmol) of chloroacetaldehyde diethyl acetal, 2.77 g (20 mmol) of potassium carbonate, 500 mg of potassium iodide and 5 ml of dimethylformamide were heated for 1 hour at 175° C. under microwave conditions. The mixture was then diluted with 2M aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried with sodium sulfate and the solvent evaporated in vacuum. The crude product was obtained in almost quantitative yield.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61][N:39]3[C:38](=[O:42])[CH:37]=[C:36]([O:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([Br:27])=[CH:33][N:32]=4)[CH:41]=[N:40]3)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: O=c1cc(OCc2ccc(Br)cn2)cn[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccc(Br)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 15b from 1.13 g (4.00 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 25b) and 1.73 g (4.00 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].O[N:16]1C2C=CC=CC=2N=[N:17]1.Cl.CN(C)CCCN=C=NCC.O.NN>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:16][NH2:17])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)cc1F
Yield: 21.5 %

Procedure:
From 3-fluoro-4-methoxycarbonylbenzoic acid (198 mg, 1 mmol), 1-hydroxybenzotriazole (HOBt) (135 mg, 1 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (WSC) (249 mg, 1.3 mmol) and hydrazine monohydrate (73 μL, 1.5 mmol), 45.6 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 50 as a white solid (yield 22%).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:17][CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH3:34].O1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:34][C:19](=[O:20])[CH:18]([NH:17][C:15]([CH:11]1[N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:14][CH2:13][S:12]1)=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Compound Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-(phenyl)acetic acid (500 mg, 1.04 mmol) was dissolved in THF (10 mL). Ammonia in dioxane (0.5N, 3.11 mL, 1.55 mmol) was added followed by HOBt (210 mg, 1.55 mmol) and DMAP (6 mg, 0.05 mmol). EDC.HCl (298 mg, 1.55 mmol) was finally added. The mixture was stirred for 5 hours at RT. As the reaction was complete, it was diluted with EtOAc, washed with 5% citric acid, NH4Cl sat, NaHCO3 sat, brine and dried over MgSO4. After filtration and evaporation of the solvents, the resulting crude product was purified by flash chromatography (Cyclohexane/EtOAc, gradient from 1:1 to 0:1). Compound Ib, e.g. N-(2-amino-2-oxo-1-phenylethyl)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide, was isolated in 90% purity by HPLC (349 mg, 80% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[N:5][N:4]=1)[CH3:2]>Br>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccccc1
Agent: Br
Product: CCc1nnc(-c2ccc(O)cc2)n1-c1ccccc1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 3.86 g of 3-ethyl-5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole and 20 ml of a hydrobromic acid solution at 48% was refluxed with stirring for one hour and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of hot water and ammonium hydroxide was added until the pH was alkaline. The mixture was stood overnight with stirring and was vacuum. The product was washed with water and dried at 90° C. under reduced pressure. The 3.65 g of product were crystallized from methanol and the mixture was iced and vacuum filtered. The crystals were washed by empasting with methanol and were dried at 90° C. under reduced pressure to obtain 3.245 g of 4-(3-ethyl-4-phenyl-4H-1,2,4-triazol-5-yl)-phenol melting at 275° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([F:24])=[CH:26][CH:27]=1)=[O:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (538 mg, 89%).