Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Cl)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+]>Cl[Cu].O>[NH:1]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](Cc1ccccc1Cl)C(=O)O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 95 °C
Reaction time: 22 h
Yield: 76.6 %

Procedure:
A flask was charged successively with 3.00 g (15.0 mmol) (S)-2-amino-3-(2-chloro-phenyl)-propionic acid, 2.17 g (15.7 mmol) K2CO3, 15 mg CuCl (2.9 mmol) and 15 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95° C. and kept at this temperature for 22 h. Samples were taken regularly and analyzed by HPLC. The conversion after 22 h was approximately 40%. Then 15 mL water was added and the mixture stirred and heated for an additional 18 h. HPLC indicated full conversion of (S)-2-chlorophenylalanine. The reaction mixture was cooled to ca 25° C. The pH of the solution was then decreased from 7.6 to ca 3.5. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2×10 mL 0.01 M HCl. Found after drying 1.88 g (11.5 mmol) (S)-2,3-dihydro-1H-indole-2-carboxylic acid. Yield 76.6%, ee>99%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(O)C.[CH2:17]([CH2:19][NH2:20])[OH:18]>O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:20][CH2:19][CH2:17][OH:18])([O-:13])=[O:12]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
25 g (0.123 mol) of 1-chloro-2,6-dinitrobenzene are placed in a three-necked, round-bottomed flask containing 180 ml of ethanol. The reaction mixture is heated to 70° C., 22.3 g (0.365 mol) of ethanolamine are added dropwise over 15 minutes and the mixture is left stirring at this temperature for 30 minutes. The temperature of the reaction mixture is left to return to room temperature and 1 liter of water is then added. The product crystallizes, is sucked dry, is washed with water and is dried. There are obtained 25 g of product which is used as is in the following stage.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].II.[Br:22]Br>C(O)(=O)C.O>[C:1]([O:4][C:5]1[CH:12]=[C:11]([Br:22])[C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1OC(C)=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=O)c(Br)cc1OC(C)=O
Temperature: 45 °C

Procedure:
To a mixture of 4-acetoxy-3-methoxybenzaldehyde (75.7 g), anhydrous sodium acetate (76 g) and iodine (0.8 g) in acetic acid (300 ml) is added bromine (21 ml). The mixture is warmed to 45° C. for about 1 hour, then stirred stirred at room temperature for 3 days, poured into water (700 ml) and filtered. The solid is dissolved in toluene and the solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is recrystallized twice from hexanes to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)[CH:16]=[CH:17][N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 8 %

Procedure:
To a solution of 1-(4-chlorophenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 764 mg, 2.52 mmol) in 20 mL of methanol was added phenylhydrazine (408 mg, 3.78 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-chlorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (70 mg, 8% for two steps) as a brown solid.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:18])[CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:18][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:17][CH2:16][CH2:15]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC1(N)CCC1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCC1
Yield: 70.4 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo [1,5-a]pyrid-6-yl)oxirane and 972 mg (11.42 mmol) of (1-methylcyclobutyl)amine [J. Am. Chem. Soc., 83, 2723 (1961)] in 0.9 ml of absolute ethanol was heated at 70° C. for 3 hours with stirring under nitrogen. The reaction mixture was then concentrated to dryness (wt. 547 mg) and the residue purified by preparative Tlc on silica gel (95:5:1 methylene chloride:methanol:conc. ammonium hydroxide) to give 402 mg of product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)c(OC)c1
Yield: 82.7 %

Procedure:
A mixture of 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (14.5 g, 55.8 mmol) and thiourea (4.32 g, 56.7 mmol) in 95% EtOH (110 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4-dimethoxyphenyl)thiazol-2-amine (10.9 g) as yellow solids in 62% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.53 (s, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 6.67-6.63 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:11][C:9]1[N:8]=[C:7]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:25][C:24]=3[CH3:26])[CH2:20][CH2:21]2)[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 176-178° C.; 1H NMR (300 MHz, CDCl3): δ 6.70 (s, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.57 (d, J=2.2 Hz, 1 3H), 4.98-4.91 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.77 (s, 3 H), 3.02 (t, J=7.7 Hz, 2 H), 2.04 (s, 3 H), 1.74-1.64 (m, 2 H), 1.33 (d, J=6.9 Hz, 3 H), 0.90 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H23N3O2Cl (M+H)+: 348.1479; found m/z 348.1490.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[CH2:1]([C:13]([CH2:12][CH2:11][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1CCOC1
Reactant: CCCCCCCC[Mg]Br
Product: CCCCCCCCC(=O)CCCCCCCC
Reaction time: 3.5 h
Yield: 88 %

Procedure:
To a solution of the product of Example 1 (4.0 g, 14.5 mmol) in THF (100 mL) was added a solution of 2M octylmagnesium bromide in THF (20 mL, 40 mmol) dropwise. After stirring for 3.5 hr, the solution was quenched with saturated NH4Cl, acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 7.5% ethyl acetate in hexanes gave the bis-octyl ketone (III) (4.86 g, 88%) as an oil. 1H NMR (300 MHz, CDCl3) δ 4.55 (s, 2H, CH), 2.64 (dt, 4H, CH2), 1.62 (m, 4H, CH2), 1.42 (s, 6H, CH3), 1.27 (broad s, 20H, CH2), 0.88 (t, 6H, CH3); MS (CI,NH3) m/e 383 (M+1)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:11][O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[N:17]=1)=[O:24]
Reactant: OCCC(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cccc(COCCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3,3-Trifluoro-propan-1-ol (0.214 g) in THF (8 mL) was treated under an argon atmosphere with sodium hydride (0.1 g, 60% suspension in oil) and stirred for 1 h at RT. N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide, 0.142 g, product of example 120 step A], was added and the mixture was heated at 85° C. for 2.5 h. The reaction mixture was cooled, partitioned between ice water and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered and evaporated to give 2,2-dimethyl-N-[6-(3,3,3-trifluoro-propoxymethyl)-pyridin-2-yl]-propionamide (0.21 g) as a light brown oil. MS (ESI): 305.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:30])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:30])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F
Yield: 42 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-5-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide (0.300 g), KOH (0.100 g), water (2 ml) and THF (10.0 mL) to afford 0.100 g of the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[C@@H:6]([CH3:11])[O:5][C:3]1=[O:4].[OH-:12].[Na+]>CO>[NH2:1][C@@H:2]([C@H:7]([C:8]([OH:10])=[O:9])[C@H:6]([OH:5])[CH3:11])[C:3]([OH:12])=[O:4]
Reactant: C[C@H]1OC(=O)[C@@H](N)[C@@H]1C(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@@H](C(=O)O)[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
2.07 g of 2(S)-amino-3(S)-carboxy-4(R)-pentanolide are suspended in 10 ml of methanol and dissolved by the addition of 13 ml of 2N aqueous sodium hydroxide solution with stirring at room temperature. The solvent mixture is distilled off and acetonitrile is added to the oily residue. The crystals which gradually form are filtered off, washed with a small amount of acetonitrile and dried under a high vacuum. The disodium salt of the title compound remains behind, [α]D20 =-9.0° (1% in water). 1H-NMR (D2O): 1.21 (3H, d 6.4 Hz), 2.54 (1H, dxd 6.4 and 8.4 Hz), 3.49 (1H, d 6 Hz), 3.97 (1H, dxq 8.4 and 6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:31].[CH2:32](O)[CH3:33]>>[ClH:31].[ClH:31].[CH2:32]([O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)[CH3:33]
Reactant: O=C(O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 27.5 °C
Reaction time: 4 h

Procedure:
To a stirred solution of {4-{4-[bis-(4-fluorophenyl)methyl]-piperazin-1-yl}-(Z)-but-2-enyloxy}acetic acid (1.0 g, 0.0024 mol) in ethanol (20 ml), is added a solution of anhydrous ethanolic HCl till pH is 1-2. The solution is refluxed for around 2 hrs, cooled to 25-30° C. and stirred for 4 hrs. The crystallized solid is filtered, washed with ethanol (2×5 ml), and dried in oven at 60-65° C. to get the product.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[C:15]3=[CH:16][CH:17]=[N:18][C:19]4[CH:20]=[CH:21][C:22](=[O:23])[N:13]([C:14]=43)[CH2:12]2)[CH2:6][CH2:5]1.[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1>>[ClH:1].[S:24]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH:11]4[C:15]5=[CH:16][CH:17]=[N:18][C:19]6[CH:20]=[CH:21][C:22](=[O:23])[N:13]([C:14]=65)[CH2:12]4)[CH2:6][CH2:5]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCS2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4nccc2c43)CC1
Agent: Cl
Product: O=c1ccc2nccc3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCS3)CC1

Procedure:
The free base of the title compound was synthesised from 4-[(4-amino-1-piperidinyl)methyl]-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one dihydrochloride salt and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 2(h).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8](N)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].C(ON=O)CC(C)C.C[Si](C)(C)[Br:33].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8]([Br:33])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(N)nc1C(F)(F)F
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a suspension of 2.11 g 5-amino-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester in 20 ml dibromomethane was added 1.59 g isoamylnitrite and the mixture was cooled to 0° C. To the resulting suspension was added 2.922 g trimethylbromosilane and the mixture was stirred at 0° C. for 10 min (no conversion by HPLC) and at room temperature for 3 h. To the dark reaction mixture was added another 1.59 g isoamylnitrite and the mixture was stirred at room temperature for 6 h. The dark reaction mixture was pored onto ice and ca 20 ml 10% sodium bicarbonate and the product was extracted with dichloromethane (2.64 g raw material which crystallized) and purified by chromatography on silica gel (20 g hep:EE=9:1 to 1:1) to yield 2.290 g of the title compound as white crystals. MS (M+H at 396.8 and 394.9).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:35]3[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: O=C(c1cccnc1)c1ccc(Cl)c(Cl)c1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cccnc3)c3ccc(Cl)c(Cl)c3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (78.6 mg, 0.183 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (3,4-dichlorophenyl)(pyridin-3-yl)methanone (50.2 mg, 0.199 mmol, Intermediate 90: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 20 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (d, J=2.0 Hz, 1H), 8.32 (dd, J=4.8, 1.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.5, 0.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 2H), 7.53-7.48 (m, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.17 (dd, J=7.8, 4.7 Hz, 1H), 7.06 (dd, J=8.4, 2.2 Hz, 1H), 6.39 (dd, J=2.4, 1.9 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 3H); MS m/e 601.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([O:31]C)=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16])[CH3:3].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:3][CH:2]([NH:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([OH:31])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16])[CH3:1]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CNC(C)C)ccc2c1OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)NC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 100 °C
Yield: 34.3 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 69, 0.12 g) and lithium hydroxide monohydrate (0.1 g) in a mixture of dioxane (10 mL) and water (5 mL) was stirred and heated at 100° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was acidified to pH4 with formic acid then extracted with a mixture of ethyl acetate and THF (1:1). The organic phase was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (2 mL) and hexane was added (10 mL). The solid was collected by filtration and washed with ether to give (1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.04 g) as an off white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[CH2:19]([O:21][C:22]1[C:23]([C:28](O)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)[CH3:20].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:21][C:22]1[C:23]([C:28]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCOc1cccnc1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cccnc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 150 mg, 0.53 mmol), 3-ethoxypyridine-2-carboxylic acid (CAS number 103878-09-7; 106 mg, 0.64 mmol), EDC (153 mg, 0.80 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (108 mg, 0.80 mmol) and triethylamine (0.222 ml, 1.59 mmol) in DCM (1 ml) was stirred at room temperature over the weekend. The mixture was partitioned between ethyl acetate (50 ml) and water (20 ml). The organics were washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (basic silica, 30-100% ethyl acetate/petrol) and then by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][C:17]=3[NH:27]C(=O)OC(C)(C)C)=[O:14])=[CH:11][CH:10]=2)[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:35]=[CH:36][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[CH3:37])[CH2:4]2)=[CH:10][CH:11]=1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
To a solution of compound 8 (0.198 g, 0.38 mmol) in DCM (3 mL) was added neat trifluoroacetic acid (1 mL). The solution was allowed to stir at room temperature for 90 min, concentrated (without heating), taken up in AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated to give title compound 9 (0.038 g, 24% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:21])([F:20])[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=O)=[CH:4][C:3]=1[CH3:22].S(C)C.N#N.C([O-])(O)=O.[Na+]>C1COCC1.CO>[F:20][C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[C:3]([CH3:22])[CH:4]=1)([F:21])[CH2:12][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C(F)(F)C(=O)N2CCOCC2)cc([N+](=O)[O-])c1N
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1cc(C(F)(F)CN2CCOCC2)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
To a solution of 2-(4-amino-3-methyl-5-nitro-phenyl)-2,2-difluoro-1-morpholin-4-yl-ethanone (945 mg, 3 mmol) in anhydrous THF (15 mL) was added BH3.S(CH3)2 (1 mL, 790 mg, 10.4 mmol) dropwise and slowly under N2 at 0° C. The mixture was stirred under N2 at the room temperature for 19 h and then refluxed under N2 for 1.5 h. After being cooled to 0° C., MeOH (2 mL) was added dropwise and slowly. The reaction mixture was poured into 20% aqueous NaHCO3 solution (150 mL) and extracted with EtOAc (3×50 mL). The organic extract was washed with brine (2×10 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (2:3 hexanes/EtOAc) to afford the title compound (740 mg, 82%). 1H NMR (CDCl3) δ2.29 (s, 3H), 2.56-2.61 (4H), 2.93 (t, J=12 Hz, 2H, CH2CF2), 3.62-3.63 (4H), 6.34 (br s, 2H NH), 7.44 (s, 1H), 8.25 (s, 1H). (s, 1H). ESI-MS m/z 302 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][C:21]1([CH3:26])[CH2:25][O:24][CH2:23][NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([N:22]3[C:21]([CH3:26])([CH3:20])[CH2:25][O:24][CH2:23]3)=[O:19])=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CC1(C)COCN1
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N2COCC2(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=367.4 [MH+].