Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([O:18]C)[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([OH:18])[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:9][CH2:10]1
Reactant: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of sodium iodide (3.75 g) in acetonitrile (150 mL) was added chlorotrimethylsilane (3.17 mL) with stirring at room temperature for 30 min. Then, 1-(cyclopropylmethyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1.613 g) was added, and the mixture was stirred for 30 min at the same temperature and further refluxed for 4 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with diisopropyl ether, collected by filtration, washed successively with ethyl acetate and diisopropyl ether, and dried to give the title compound (1.23 g) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]([C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33](OCC)=[O:34])[CH2:29][CH2:28]2)[C:11]2[C:16]([N:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[N:12]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH2:33][OH:34])[CH2:29][CH2:28]2)[C:11]2[C:16]([N:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[N:12]=2
Reactant: CCOC(=O)[C@H]1CC[C@H](n2c(Nc3ccccc3F)nc3cnc(Nc4ccc(OC)cc4)nc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc3nc(Nc4ccccc4F)n([C@H]4CC[C@H](CO)CC4)c3n2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Ethyl 4-{8-[(2-fluorophenyl)amino]-2-[(4-methoxyphenyl)amino]purin-9-yl}-trans-cyclohexanecarboxylate (0.28 g, 0.55 mmol) was dissolved in 9 mL of THF and cooled to 0° C. (under nitrogen atmosphere). 1.38 mL of 1.0M LiAlH4 in THF was added dropwise. The solution turned a dark orange as the LiAlH4 was added. The reaction mixture was stirred for about 5 h and quenched by the addition of 40 mL of water. The reaction was extracted three times with ethyl acetate. Organics were combined and dried with magnesium sulfate, filtered and the solvent was removed in vacuo. The crude reaction mixture was then purified using reverse-phase preparative HPLC (20-80% acetonitrile/water (0.1% TFA) over 30 min) to obtain 0.126 g of the desired product (50% yield) after neutralization of the TFA salt. ES-MS: 463 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.Cl.[CH3:11][P:12]1(=[O:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][N:15]2[CH2:16][CH2:17][P:12](=[O:18])([CH3:11])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CP1(=O)CCNCC1
Reactant: BrCc1cccc(Br)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)CCN(Cc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (500 mg, 1.99 mmol), 4-methyl-1,4-azaphosphinane 4-oxide hydrochloride (406 mg, 2.39 mmol, prepared according to the method described in WO 2008/010985), and DIEA (522 μL, 2.99 mmol) were combined in DMF (5.0 mL) and stirred at room temperature overnight. The solvent was then evaporated in vacuo and the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA) to afford the title compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1.N1C=CC=CC=1.[SH2:25]>C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[S:25])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1
Reactant: Cc1cc2nncn2nc1-c1ccc(C#N)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc2nncn2nc1-c1ccc(C(N)=S)cc1

Procedure:
A 2.1 g. portion of p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as in Example 1) is partially dissolved in a solvent mixture of 50 ml. of pyridine plus 5.0 ml. of triethylamine. Hydrogen sulfide gas is bubbled into the reaction mixture over a 3 hour period during which time the color of the reaction mixture changes from yellow to green. A solid begins to form in the reaction mixture approximately 15 minutes after the addition of the hydrogen sulfide gas is begun. The mixture is then filtered and the yellow solid is washed with petroleum ether to afford the product of the example as a bright yellow solid, m.p. 268°-272° C.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][C:31]([F:40])=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:33]=2)[CH2:24][CH2:23]1>>[F:40][C:31]1[CH:30]=[CH:29][C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:27][CH2:26]2)=[CH:33][C:32]=1[NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 51 was prepared from 2,2-diphenylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.27–8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50–7.39 (m, 1H), 7.39–7.16 (m, 7H), 7.12–6.90 (m, 2H), 6.79–6.60 (br, 1H), 4.94–4.61 (br, 1H), 3.60–3.22 (m, 4H), 2.89–2.76 (m, 2H), 2.76–2.55 (m, 4H), 2.55–2.34 (m, 3H), 2.14–1.82 (m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J=6.4 Hz); ESMS m/e: 530.4 (M+H)+; Anal. Calc. for (HCl salt) C33H41ClFN3O2.0.24CHCl3.0.96H2O: C, 65.23; H, 7.11; N, 6.86. Found: C, 64.96; H, 7.36; N. 6.87.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][C:20]([NH:22][C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][C:20]2[O:31][C:29](=[O:30])[C:23]3([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccccc1)NC1(C(=O)O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 784 mg (3 mmol) of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid obtained in Reference example 2 in 20 ml of methylene chloride. After the mixture was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 625 mg (86%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([CH3:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH2:1]([N:5]1[C:10]([CH3:11])=[C:9]([N+:15]([O-:17])=[O:16])[C:8](=[O:12])[N:7]([CH3:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.69 g (8.61 mmol) of 1-butyl-3,6-dimethyl-1H-pyrimidine-2,4-dione in 30 mL concentrated H2SO4 at 0° C. was added 1.7 mL fuming HNO3 in drops over 10 min. After stirring at 0° C. for an additional 30 min, the reaction mixture was poured into 300 mL of ice, extracted with 2×150 mL CH2Cl2, and the combined organics were dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1), gave 1.72 g (7.13 mmol, an 83% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.99 (t, J=7.3 Hz, 3H), 1.46 (hex, J=7.3 Hz, 2H), 1.62-1.73 (m, 2H), 2.42 (s, 3H), 3.39 (s, 3H), 3.92 (t, J=7.4 Hz, 2H); IR (KBr, cm-1): 2961s, 2874s, 1722s, 1670s, 1620s, 1363s, 1224m; MS (ES) m/z (relative intensity): 242 (M+ +H, 100). Anal. Calcd for C10H15N3O4 : C, 49.79; H, 6.27, N, 17.42. Found: C, 49.47; H, 6.03; N, 17.37.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:16](I)[CH2:17][CH2:18][CH3:19].N1C(C)=CC=CC=1C>>[CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH3:14])[N:6]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)Nc1ccc(Cl)cc1
Solvent: Cc1cccc(C)n1
Product: CCCCN(c1ccc(Cl)cc1)[C@@H](C)C(=O)OCC
Temperature: 135 °C

Procedure:
N-(4-Chlorophenyl)alanine ethyl ester (4.5 g, 0.02 mol), n-butyl iodide (3.6 g, 0.02 mol) and 2,6-lutidine (2.5 g, 0.025 mol) were sealed in a glass tube and the contents were heated at 135° C. for 48 h. The tube was then cooled, and the contents were partitioned between 250 mL ethyl acetate and 200 mL brine. The organic layer was separated, dried over anhyd. sodium sulfate, and concentrated at reduced pressure. The resulting oil was chromatographed on silica gel using heptane:THF (4:1) as the eluant. The ester was isolated as a colorless oil (2.5 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: Cc1ccc(C)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3C)cccc2c1N
Yield: 83.1 %

Procedure:
Using method B, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.702 mmol) and 2,5-dimethylphenylboronic acid (150 mg, 1.00 mmol) were reacted to afford the title compound (195 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.87 (m, 1H), 7.75-7.64 (m, 2H), 7.23-7.07 (m, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 2.35 (s, 3H), 2.01 (s, 3H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=335 HPLC 1.98 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35]C3)=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1ccccn1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4ccccn4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using pyridine-2-yl-acetic acid and 6-((S)3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.76 min, [M+1]+ 494. Potency class C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([C:24]([NH2:31])([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:31][C:24]([C:21]3[N:20]=[C:19]([CH3:18])[O:23][N:22]=3)([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OC(C)CF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (52.6 mg, 71%); MS (ESI, m/z): 441.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:9]=3[CH2:10][CH2:11][C:4]=2[CH:3]=1.Br[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([N:6]1[CH2:7][C:8]2[CH:15]=[CH:14][C:13]([C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[C:33]([NH2:35])=[O:34])=[CH:12][C:9]=2[CH2:10][CH2:11][C:4]2[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]1=2)(=[O:27])[CH3:26]
Reactant: CC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CCc2cc(Cl)ccc21
Reactant: NC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)N1Cc2ccc(-c3ccccc3C(N)=O)cc2CCc2cc(Cl)ccc21
Temperature: 80 °C
Yield: 57.6 %

Procedure:
A 2 mL conical vial was charged with Example 22B (10 mg, 0.024 mmol), 2-bromo-benzamide (7 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg). The vial was evacuated and purged with argon. EtOH (0.5 mL) and toluene (0.5 mL) were added, followed by 2M aqueous Na2CO3 (0.036 mL, 0.072 mmol). The reaction was heated to 80° C. until disappearance of the starting material was noted. The reaction was cooled to room temperature and concentrated. The product was purified by reversed-phase HPLC to afford 2-(5-Acetyl-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocin-9-yl)-benzamide (5.6 mg, 58%). HPLC Rt=1.62(b) min. m/z=405 (M+H+).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34]\[CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35]/[CH:34]=[C:33](\[C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:19]=1
Reactant: OC/C=C(/c1ccccc1)c1ccc(Br)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 650 mg (74%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1cncn1
Temperature: 25 °C
Yield: 72 %

Procedure:
138 g (2 mol) of 1,2,4-triazole were added in portions to 276.4 g (2 mol) of ground potassium carbonate and 269.2 g (2 mol) of α-chloropinacolin in 500 ml of acetone at room temperature, the internal temperature rising to the boiling point. The reaction mixture was stirred under reflux for 5 hours and then cooled to room temperature. It was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. After adding benzene, the oily residue crystallized. 240.8 g (72% of theory) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 62°-64° C. were obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:21])[C:7]([S:18]([CH3:20])=O)=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H](S)[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24].CC(N(C)C)=O>CN(C)C=O>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:20]([S:18][C:7]2[C@H:6]([CH3:21])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (150 mg) and silica gel (300 mg) in N,N-dimethylformamide (1.5 ml) was added a solution of (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)-4-mercaptopyrrolidine (150 mg) i dimethylacetamide (1.45 g). The mixture was stirred for 2 hours at ambient temperature. Silica gel was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([CH3:23])[N:20]=1)=[O:25]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Product: Cc1cc(Cl)cc(C(=O)N(C)c2cnccc2-c2ccccc2C)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-chloro-6-methylpyridine-2-carboxylic acid (CAS RN 30235-19-9). Colorless solid (35%). MS (ESI): m/z=352.12 [M+H]+.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]>ClCCl>[CH2:9]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH3:10]
Reactant: COC(=O)CC(=O)Cl
Reactant: CCNc1ccccc1
Solvent: ClCCl
Product: CCN(C(=O)CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Dichloromethane was added to a dry round bottom flask at 20-25° C. under nitrogen atmosphere. Methyl 3-chloro-3-oxo-propanoate (2.59 ml, 24.15 mmol) was added, followed by N-ethylaniline (2.97 ml 24.13 mmol), and the solution was stirred at r.t. for 14 h, then the solvent was removed under reduced pressure to obtain a yellowish oil. Yield: 100%. The purity of the isolated product: 98% (HPLC, area %).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC(C)=C)=[CH:7][C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]>CN(C)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]2[O:15][C:6]([CH3:20])([CH3:7])[CH2:5][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:21])[CH3:22])(=[O:3])[CH3:2]
Reactant: C=C(C)COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Solvent: CN(C)c1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-1-(2-methyl-2-propenyloxy)benzene (2.22 g) was dissolved in N,N-dimethylaniline (8 ml) and the solution was refluxed under a nitrogen atmosphere for 36 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and, after addition of 1N HCl (5 ml) and diethyl ether (10 ml), stirring was continued for 15 min. The organic layer was separated and the aqueous layer was subjected to extraction with diethyl ether. The combined extracts were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (5% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2,2-dimethyl-2,3-dihydrobenzofuran [1.19 g (yield, 54%)] as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@H:14]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:15][C@@H:14]1[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(F)ccc2O[C@H](Cc2ccccc2)[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared by hydrogenation of (−)-(6R,7S)-6-benzyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 287.1 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[C:3]=2[C:21]#[N:22])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile, compound C, (1 eq, 0.250 g, 0.80 mmole) in N,N′-dimethylformamide was added commercially available piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.164 g, 0.88 mmole) and treated with 60% NaH oil dispersion (1.5 eq, 0.029 g, 1.2 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq, (1 ml) then H2O (5 ml), A solid formed that was collected and dried. No further purification was necessary, afforded 4-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.325 g, 88%, calc M+H 463, obs M+H 463).