Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Li][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[C:13]([C:18]([O:20]CC)=O)=[N:14][NH:15][C:16]=1[CH3:17]>C1COCC1>[CH2:1]([N:5]([CH2:7][CH2:8][CH2:9][CH3:10])[C:18]([C:13]1[C:12]([Cl:11])=[C:16]([CH3:17])[NH:15][N:14]=1)=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Reactant: CCCCN
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of n-butylamine (900 μL, 5.30 mmol) in THF (4.0 mL) was added n-BuLi (5.0 mL, 7.95 mmol, 2.5M solution in hexanes) at −78° C. After stirring at −78° C. for 30 min, a solution of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (500 mg, 2.65 mmol) in 2.0 mL of THF was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature overnight and quenched with sat. aq. NH4Cl solution. The aqueous layer was extracted with CH2Cl2 (3×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. Purification using flash column chromatography (gradient from 0% to 7% MeOH/CH2Cl2) provided the title compound (589 mg, 82%) as a colorless oil. 1H NMR (CD3OD) δ 3.51 (t, J=7.4 Hz, 2H), 3.38-3.32 (m, 2H), 1.68-1.62 (m, 2H), 1.56-1.50 (m, 2H), 1.45-1.38 (m, 2H), 1.22-1.15 (m, 2H) 0.98 (t, J=7.4 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 272.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (780 mg, 2.4 mmol) was dissolved in N,N-dimethylformamide (15 mL) and to this was added potassium hydrogen carbonate (260 mg, 2.6 mmol) followed by benzyl bromide (281 μL, 2.4 mmol) and stirring continued at ambient temperature for 6 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2×60 mL). The organic extracts were washed with water (2×20 mL), brine, dried over sodium sulfate and filtered through a layer of silica gel. The filtrate was concentrated in vacuo and the residue crystallized from 100% hexane to give (4-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (500 mg, 50%).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=O)[N:4]2[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:25])[N:4]2[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1c2ccccc2NC[C@@H]2CCCN12
Solvent: Cc1ccccc1
Product: S=C1c2ccccc2NC[C@@H]2CCCN12
Yield: 73.4 %

Procedure:
To 50 ml of toluene, there were added 2.02 g of (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 24 and 4.04 g of the Lawesson's reagent and the mixture was heated under reflux for one hour. After cooling the reaction solution, it was concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/acetone (99/1). The elute was concentrated and recrystallized from ethyl acetate to give 1.6 g (yield 73.3%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nn3)CC2)c(C)c1
Yield: 9.3 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and pyrrolidin-2-one (46 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (16 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C(10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15]N[CH2:13][CH2:12]1.O>CN1CCCC1=O>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([N:1]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:3]1
Reactant: Nc1csc2ccccc12
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(N3CCNCC3)csc2c1

Procedure:
To a solution of methyl 3-aminobenzothiophene-2-carboxylate [prepared by the method of J. R. Beck, J. Org. Chem. 1972, 37, 3224] (6.5 g, 31.4 mmol) in N-methylpyrrolidinone (30 ml) was added 1-methylpiperazine and the reaction mixture was heated to 178° C. for 4 h. After cooling the mixture was poured into water and the product extracted with diethyl ether (3×100 ml), the extracts were washed with water (1×100 ml) and brine (1×100 ml), combined and dried (MgSO4). Concentration of the extracts yielded 3-aminobenzothiophene (5.9 g), which was used without purification. To a solution of 3-aminobenzothiophene (5 g, 32 mmol) in N-methylpyrrolidinone (50 ml) was added piperazine (8.7 g, 102 mmol) and the mixture heated to reflux under nitrogen for 14h. Cooled and poured into water and extracted with dichloromethane (4×100 ml). The extracts were washed with brine (50 ml), combined and dried (MgSO4). On concentration of the extracts a white solid came out of solution which was collected by filtration to yield the title compound (0.78 g, more product left in solution); δH (DMSO-d6 +TFA), 3.3 (8H, m, 4×piperazinyl CH2), 7.08 (1H, s, 3-H), 7.39 (2H, m, 2×ArH), 7.83 (1H, m, ArH), 7.95 (1H, m, ArH), and 9.30 (1H, br s, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.000 g, 4.00 mmol) in chloroform (15 mL) was added thionyl chloride (3.0 mL, 40.00 mmol). The reaction mixture was left stirring at reflux for 3 days and then concentrated in vacuo. The obtained crude solid, 4-chlorocarbonylpiperidine-1-carboxylic acid tert-butyl ester, was used without further purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Tetrapropylammonium perruthenate (9.4 mg, 0.027 mmol) was added to a mixture of (1S,4R)-4-(tert-butyldimethylsilanyloxy)cyclopent-2-enol prepared, according to Tetrahedron Letters, Vol. 37, No. 18, 1996, pp. 3083-6, (118.6 mg, 0.54 mmol), 4-methylmorpholine N-oxide (94.9 mg, 0.81 mmol) and crushed 4 Å sieves (270 mg) in CH2Cl2 (10 mL). The mixture was stirred for 30 min and was passed through a plug of silica gel with CH2Cl2. The filtrate was concentrated in vacuo to give 100 mg (86%) of the above titled compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30](Cl)[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][C:44]1[S:45][C:46](B2OC(C)(C)C(C)(C)O2)=[C:47]([CH3:49])[N:48]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.O>C(#N)C>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30]([C:46]5[S:45][C:44]([CH3:43])=[N:48][C:47]=5[CH3:49])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ncc(-c2sc(C)nc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 130 °C
Yield: 8.9 %

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 1, 100 mg, 0.161 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (38.6 mg, 0.161 mmol) and K2CO3 (66.9 mg, 0.484 mmol) were mixed with 1.5 mL of 4/1 dioxane/water. The mixture was evacuated and charged with nitrogen three times, then {2-[2-(amino-κN)ethyl]phenyl-κC1}(chloro)[di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine]palladium (tert-Butyl X-Phos Precatalyst) (8.3 mg, 0.016 mmol) was added. The reaction was sealed and then heated for 25 minutes at 130° C. in a microwave reactor. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 21.2×150 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL), then eluted with 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give 10 mg product. LCMS (M+H)+: 697.4. 1H NMR (CDCl3, 500 MHz): δ 8.33 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.80 (s, 2H), 7.55 (d, J=2.1 Hz, 1H), 5.71 (d, J=8.5 Hz, 1H), 5.58 (m, 0.5H) 5.47 (m, 0.5H), 4.78 (d, J=17.1 Hz, 1H), 4.54 (m, 2H), 4.37 (m, 3H), 4.06 (d, J=18.4 Hz, 1H), 4.04 (s, 3H), 2.75 (s, 3H), 2.51 (s, 3H), 0.79 (d, J=6.5 Hz, 3H). RTA IC50: 3 nM
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.S([CH2:28][N+:29]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>C(COC)OC.C(O)(C)(C)C>[C:28]([CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1)#[N:29]
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(=O)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(C#N)CC1
Reaction time: 3 h

Procedure:
To a −15° C. solution of 1 eq. of N-[2-[4-oxocyclohexyl]propyl] 2-propanesulfonamide (see Preparation 2) and 1 eq. of tosylmethyl isocyanide in dimethoxyethane is added a solution of 2.8 eq. of potassium t-butoxide in t-butanol. The cooling bath is removed and the mixture is stirred for three hours. The mixture is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to provide the crude material. Chromatography (silica gel) of the crude material affords the purified title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[CH2:12]([C@H:14]([NH:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:25]=1[O:40][CH2:41][CH2:42][NH2:43])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[O:40]([CH:25]([CH3:24])[CH3:26])[CH:41]([CH3:42])[CH3:3].[CH2:12]([C@H:14]([NH:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:25]=1[O:40][CH2:41][CH2:42][NH:43][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(O)Cc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)OC(C)C
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)Cc2cccnc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 116.3 %

Procedure:
Prepared as described in Example 26 from 0.41 g (2.4 mmol) of 3-pyridylacetic acid hydrochloride, 1.0 g (2.4 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4), 0.33 ml (2.4 mmol) of TEA, 0.64 g (4.7 mmol) of HOBT and 0.58 g (2.8 mmol) of DCC. The work up and the purification of the reaction mixture were conducted as described in Example 26. After trituration with i-Pr2O, 0.76 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[C:3]1=[O:24].CCN(C(C)C)C(C)C.Cl.Cl.[NH2:43][C:44]([CH3:52])([CH3:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48].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(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19](=[O:21])[NH:43][C:44]([CH3:52])([CH3:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:22][CH:23]=2)[C:3]1=[O:24]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)NC(C)(C)CN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 0.896 g of the compound obtained in step B of EXAMPLE 262 in 10 ml of DCM is cooled to 0° C. and 0.36 ml of DIPEA is added, followed by 0.445 g of 2-amino-1-(diethylamino)-2-methylpropane dihydrochloride and then by 1.14 ml of triethylamine and 0.906 g of BOP. The mixture is stirred for 1 hour at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with a 5% solution of potassium carbonate, with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using AcOEt and then an AcOEt/MeOH mixture (80/20; v/v) as the eluent to give 0.12 g of the expected product after crystallization from a DCM/hexane mixture. M.p.=59° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:50][C:51]1[CH:55]=[CH:54][N:53]([CH2:56][C:57]([CH3:60])([OH:59])[CH3:58])[N:52]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:50][C:51]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]([OH:59])([CH3:58])[CH3:60])[N:52]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3c2CCCC3)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3CCCC4)cc2=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 39, 1.0 g, 2.61 mmol) in methylene chloride (26 mL, 0.10 M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (470 μL, 2.65 mmol) and 1-hydroxybenzotriazole (370 mg, 2.73 mmol). The solution was stirred at 25° C. for 2.5 h. After this time, the reaction was treated with a slurry of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 490 mg, 3.15 mmol) in methylene chloride at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (250 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×250 mL), a saturated aqueous sodium bicarbonate solution (1×250 mL), water (1×250 mL), and a saturated aqueous sodium chloride solution (1×250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 115 g, 35-75% ethyl acetate/hexanes gradient) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionamide (730 mg, 54%) as a white solid; ES+-HRMS m/e calcd for C29H37N5O4 [M+H+] 520.2919, found 520.2920. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.78 (m, 12H), 1.91 (m, 1H), 2.27 (m, 1H), 2.50 (m, 2H), 2.78 (m, 2H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (dd, J=4.3, J=10.9 Hz, 1H), 5.57 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:25]=[CH:24][C:11]3/[C:12](=C/C#N)/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:29]([CH3:30])[C:4]=2[N:3]=1.[OH-:37].[Na+].Cl.[CH2:40]([OH:42])[CH3:41]>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:25]=[CH:24][C:11]3/[C:12](=[CH:41]/[C:40]([OH:37])=[O:42])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:29]([CH3:30])[C:4]=2[N:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: Cl
Agent: [Na+]
Product: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Yield: 41 %

Procedure:
Compound 53 (80 mg, 0.17 mmol) obtained in Example 53 was suspended in ethanol (2 mL), 10 mol/L aqueous sodium hydroxide solution (3.1 mL) was added, and the mixture was stirred under reflux for 3 days. Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=98/2 to 90/10) to give the title compound (compound 55) (34 mg, 41%).
Reaction SMILES: [ClH:1].N([O-])=O.[Na+].[C:6]([O:9][C:10]1[C:11]([CH3:33])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28](N)=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[O:32])(=[O:8])[CH3:7].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>O.C1C=CC=CC=1.CC(C)=O>[C:6]([O:9][C:10]1[C:11]([CH3:33])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:36][CH:35]([Cl:1])[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[O:32])(=[O:8])[CH3:7]
Reactant: Cl
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(N)cc1)O2
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reaction time: 0.5 h

Procedure:
3 ml of concentrated hydrochloric acid and then an aqueous solution of 700 mg of sodium nitrite in 1.1 ml of water were added dropwise to a mixture of 2.1 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman-4-one and 26 ml of acetone, whilst cooling with ice. The mixture was stirred for 30 minutes at the same temperature. 7 g of ethyl acrylate were then added, after which cuprous oxide was added gradually, while keeping the reaction temperature at 30°-35° C. The reaction mixture was then stirred for 1 hour at room temperature. Water and benzene were added to the reaction mixture. The benzene layer was separated, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off and the residue was subjected to silica gel column chromatography, eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to yield ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5].[CH2:18]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:2][O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][C@@H:27]([C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:30])[CH3:29])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(O[C@H](C)C(=O)OCc2ccccc2)c2ccc(C)cc2n1
Reaction time: 2 h

Procedure:
To a solution of 1.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester hydrochloride and 0.83 g benzyl-L-lactate in 30 ml THF were added 1.81 g triphenylphosphine and 1.20 g diethylazodicarboxylate. After 2 h LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.80 g.