Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([O:25][CH:26]([CH3:27])[CH3:28])[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1OC(C)C
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1OC(C)C
Temperature: 45 °C
Yield: 80 %

Procedure:
A suspension/solution of 1,1-dimethylethyl 4-({5-methyl-4-[(1-methylethyl)oxy]-2-nitrophenyl}amino)-1-piperidinecarboxylate (D74) (0.2 mmol, 80 mg) in ethanol (10 mL) was treated with Raney Nickel, then hydrazine hydrate (2 mmol, 100 mg, 10 eq) was added dropwise over 5 min under argon at room temperature. The mixture was then heated at 45° C. for 30 min. The catalyst was then filtered off and washed with ethanol and methanol. The filtrate was concentrated under reduced pressure to give the title compound as a solid (0.16 mmol, 60 mg, 83% yield). M+H 364.3, 308.2, 264.2 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])[CH3:16]
Reactant: CCOc1cc(C#N)c(N)cc1C(F)(F)F
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C#N)ccc1C(F)(F)F
Yield: 84.8 %

Procedure:
To a solution of 2-amino-5-ethoxy-4-trifluoromethyl-benzonitrile from step 4 (31.62 g, 137.4 mmol) in dry THF (410 mL) was added isoamyl nitrite (40.4 mL, 302 mmol), and the mixture was refluxed for 16 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in sat. NaHCO3-sol., extracted three times with diethyl ether. The combined organic layers were washed with 1 N HCl and brine, dried over Na2SO4. Removal of the solvent in vacuum left an orange oil, which was purified by double Kugelrohr distillation (up to 160° C. bath temperature at 1.5 mbar) to give the title compound as a light yellow solid (25.06 g, 85%). MS (EI) 185.1 [M].
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:6])[CH2:4][CH3:5]>C(OCC)C>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: BrBr
Reactant: CCC(=O)c1cccc(C(=O)OC)c1
Solvent: CCOCC
Product: COC(=O)c1cccc(C(=O)C(C)Br)c1
Reaction time: 0.17 h

Procedure:
Bromine (4.6 ml) was dropped at 20-30° C. over 20 min. to a solution of methyl 3-propionyl-benzoate (17.24 g) in diethyl ether (0.15 L). Stirring was continued for 10 min. and the reaction mixture was then evaporated in vacuum to give methyl 3-(2-bromo-propionyl)-benzoate (25.5 g) as a yellow oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[SH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH2:18][C@@H:19]([CH3:29])[N:20]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:21][CH:22]=2)[N:16]=1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH:22]=[C:17]([C:15]2[N:16]=[C:12]([S:11][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:13][CH:14]=2)[CH2:18][C@H:19]1[CH3:29])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.58 ml, 0.58 mmol) was added at 0–5° C. to a solution of allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (172 mg, 0.58 mmol) in THF (2.0 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.21 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/4→1/3) to give allyl (4R,5S,6S)-3-[(4-{(2R)-1-[(allyloxy)carbonyl]-2-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (137 mg, 38%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.CCN=C=NCCCN(C)C.C1[CH:25]=[CH:26][C:27]2N(O)N=N[C:28]=2[CH:29]=1.[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1>CN1C(=O)CCC1>[S:36]1[CH:37]=[CH:38][N:39]=[C:35]1[NH:34][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:2]=1)=[O:12]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1nccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1nccs1)c1cn(C2CCCC2)c2ccccc12
Temperature: 120 °C

Procedure:
The crude derivative of indole-3-carboxylic acid was dissolved in NMP (5 mL). EDAC (1.09 g, 5.7 mmol) and HOBt (0.92 g, 6.84 mmol) were added. The mixture was stirred at room temperature for 1 hour before 2-aminothiazole (5.7 mmol) was added. The mixture was heated to 120° C. for 2 hours. After cooling to room temperature the reaction mixture was separated between diethyl ether (50 mL) and water (50 mL). The organic phase was washed with saturated aqueous Na2CO3 (50 mL), dried (Na2SO4) and the solvent removed in vacuo. The crude material was recrystalized from acetonitrile to give the title compound.
Reaction SMILES: COCCO[Ca]O[CH2:8][CH2:9][O:10]C.[C:12]1([Na])C=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)[OH:20]>>[C:9]([OH:10])(=[O:20])[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCCO[Ca]OCCOC
Reactant: [Na]c1ccccc1
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccccc1
Yield: 60 %

Procedure:
To the suspension was added 0.2 mole of di(2-methoxyethoxy)-calcium. On stirring the mixture, the phenyl-sodium reacted and went into solution. On carbonation, followed by treatment with dilute sulfuric acid, the mixture gave 14.6 grams of benzoic acid (a 60% yield, based on the amount of chlorobenzene used), illustrating that the sodium-containing, organometallic product had the same reactivity toward carbon dioxide as does phenyl-sodium.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:13][C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccncc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6 Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[Cl-].[NH4+]>CCOCC>[CH3:10][N:11]1[CH2:16][CH2:15][C:14]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=2)([OH:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cccc(C2(O)CCN(C)CC2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a layer of magnesium (24.3 g) covered with dry ether, a solution of m-bromotoluene (171 g, 1 mole) in dry ether (500 ml) is added under an atmosphere of nitrogen. After the addition, the mixture is heated at reflux for an hour, cooled to 0° C. and a solution of 1-methyl-4-piperidone (108 g, 950 mmoles) is added dropwise to the mechanically stirred mixture. The mixture is heated at reflux for 3 hours and allowed to stand at room temperature overnight. The suspension is cooled (<5°), 10% ammonium chloride solution is added and the mixture is extracted with ether. The combined extracts are dried (MgSO4) and evaporated. The residue is crystallized from hexane to give the title compound, mp 86°-90° C.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[CH:13]1([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14]1.Cl.[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:31]1[C:35]2=[N:36][CH:37]=[N:38][C:39]([S:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[C:34]2[CH:33]=[N:32]1.C(N(CC)CC)C>CS(C)=O>[CH:13]1([CH2:17][O:18][C:6]([N:44]2[CH2:43][CH2:42][CH:41]([S:40][C:39]3[N:38]=[CH:37][N:36]=[C:35]4[N:31]([C:22]5[CH:23]=[CH:24][C:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:26][C:21]=5[F:20])[N:32]=[CH:33][C:34]=34)[CH2:46][CH2:45]2)=[O:7])[CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: OCC1CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCN(C(=O)OCC5CCC5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Di-imidazol-1-yl-methanone (0.25 mmol, 41 mg), and cyclobutyl methanol (0.25 mmol, 24 μL) were dissolved in DMSO (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.18 mmol, 80 mg) and triethylamine (0.54 mmol, 75 μL) were added. The mixture was heated in a microwave for 5 minutes at 120° C. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided Compound A113 as a white solid (29 mg, 31%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.71 (s, 1H); 8.22 (s, 1H); 7.87 (m, 3H); 4.37 (h, 1H); 4.00 (m, 4H); 3.16 (m, 2H); 3.05 (s, 3H); 2.56 (m, 1H); 2.12 (m, 2H); 2.01 (m, 2H); 1.85 (m, 2H); 1.73 (m, 4H). Exact mass calculated for C23H26FN5O4S2 519.61, found 520.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Br:21][CH2:22][C:23](Br)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1])=[O:24]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)C1=O
Temperature: 0 °C

Procedure:
N-(2-Oxo-1-imidazolidinyl)carbamic acid, 1,1-dimethylethyl ester (12.0 g, 0.06 mmol) was dissolved in dichloromethane (75 ml) containing pyridine (5.2 g, 0.066 mol). The solution was cooled to 0° C. and treated slowly with bromoacetyl bromide (13.3 g, 0.066 mol). The solution was evaporated in vacuo to give a yellow oil. The oil was chromatographed on silica gel (~300 g) eluting with 10% ethyl acetate/dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid, 16.7 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5].C(O[CH2:34][CH3:35])(=O)C.[CH2:36](O)C>>[CH3:2][O:3][C:4]([CH:6]1[CH2:35][CH2:34][CH2:36][N:8]([C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CNc1ccc(C(=O)N2CCCC(C(=O)OC)C2)cc1[N+](=O)[O-]

Procedure:
The same procedure is used as in (1). Rf value: 0.67 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:12](=O)[CH2:11][CH:10]([C:14]([O:16]CC)=O)[C:8](=O)[CH2:7]1)=O.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].[NH2:28][NH:29][C:30]([NH2:32])=[NH:31]>C(O)CCC>[NH2:26][C:25]1[N:24]([NH2:23])[C:14](=[O:16])[C:10]2[CH2:11][C:12]3[N:31]=[C:30]([NH2:32])[N:29]([NH2:28])[C:4](=[O:3])[C:6]=3[CH2:7][C:8]=2[N:27]=1
Reactant: N=C(N)NN
Reactant: CCOC(=O)C1CC(=O)C(C(=O)OCC)CC1=O
Agent: O=C(O)O
Solvent: CCCCO
Product: Nc1nc2c(c(=O)n1N)Cc1nc(N)n(N)c(=O)c1C2
Yield: 123.2 %

Procedure:
A mixture of 12.8 g of diethyl 1,4-cyclohexanedione-2,5-dicarboxylate and 13.6 g of aminoguanidine aminoguanidine bicarbonate in 100 ml of n-butanol was heated at reflux for 9 hours. Cooling produced 17 g of the desired intermediate, mdesired intermediate, mp>300° C.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:28]=[C:24]([C:25]([NH2:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1.O>CS(C)=O>[C:25]([C:24]1[CH:28]=[C:20]([CH:21]=[CH:22][C:23]=1[OH:29])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:26])[NH2:27]
Reactant: NCCCCOc1ccc(O)c(C(N)=O)c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1OCC(O)CNCCCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
7.3 g of 2-(2,3-epoxypropoxy)benzonitrile are added to a solution of 6.7 g of 5-(4-aminobutoxy)salicylamide in 60 ml of dimethyl sulphoxide and the mixture is stirred for 1 hour in a bath at 90°. The reaction mixture is poured into 300 ml of water and extracted twice with 200 ml of ethyl acetate each time. Working up analogously to Example 23 yields crude 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2-ol as a viscous oil, the IR- and 1H-NMR-spectra of which are in concordance with the assumed structure and the Rf-value of which is 0,51 according to thin-layer-chromatography on silicagel using a mixture of ethylacetate-ethanol-conc. ammonia 24:12:4 as the eluent.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.2 mg, 0.21 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (45 mg, 0.19 mmol) in THF (1.0 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.21 mmol) in THF (1.0 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 36.5 mg (51%) of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:12]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:10][C:9]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1)=[O:11]
Reactant: Cc1ccccc1
Reactant: Nc1ccc(Cl)nc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-6-chloro-pyridine-2-carboxylic acid (636 mg) was suspended in methanol (8 mL) and toluene (22 mL) was added. A solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 2.4 mL) was added slowly to the reaction mixture. After 1 hour stirring at room temperature, another portion of (trimethylsilyl)diazomethane (550 μl) was added and the mixture was stirred for additional 45 minutes. The reaction mixture was quenched with water and extracted 3× with ethyl acetate. The combined organic layer was washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel 60, choroform/ethyl acetate=50:1, Rf=0.30) to afford 365 mg of the title compound of the formula
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1
Reactant: ClCCN1CCCCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1ccc(CN2CCN(CCN3CCCCC3)CC2c2ccccc2)cc1
Yield: 95 %

Procedure:
31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according to Example B), 25 g. of piperidino ethylchloride, 20 g. of triethylamine, and 250 cc. of acetone are boiled under reflux for 18 hours. The filtered reaction solution is freed of its solvent by concentration by evaporation. The residue is dissolved in benzene. The benzene solution is washed with water. After drying and distilling off the solvent, the base is obtained in the form of a viscous, yellow oil on distillation at 210° C./0.06 Torr. The oil crystallizes on trituration with isopropanol. After twice recystallizing the crystals from n-heptane (41 g. of yellow crystals of the melting point 85°-87° C.) are obtained. The yield is 95 % of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[CH:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.I[C:37]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[N:40]=[CH:39][CH:38]=1.C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][C:37]2[N:41]([S:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)(=[O:43])=[O:44])[N:40]=[CH:39][CH:38]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: C#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Reactant: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccnn4S(=O)(=O)c4ccc(C)cc4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of N-(5-chloro-7-ethynyl-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.140 g, 0.28 mmol ), 5-iodo-1-[(4-methylphenyl)sulfonyl)-1H-pyrazole (0.147 g, 0.42 mmol) and diisopropylamine (0.078 ml, 0.56 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this mixture was added copper (I) iodide (0.016 g, 0.084 mmol) and bis(triphenylphospine)palladium (II) chloride (0.039 g, 0.056 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was filtered and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a yellow solid (0.103 g, 51%). Mass Spectrum: M+H+ 717 and M+H− 715.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][N:4]([C:7](=[O:16])[CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])[CH2:3]1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:13]2[CH2:12][CH2:11][N:10]([CH:8]([CH3:9])[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:1])([F:17])[CH2:3]3)=[O:16])[CH2:15][CH2:14]2)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: CC(C(=O)N1CCC(F)(F)C1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)N1CCC(F)(F)C1)N1CCN(C(=O)c2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a stirred solution of 12 mg (0.049 mmol) of 4-(2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl)piperazine (TEA salt), and 20 mg (0.049 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 mL anhydrous N,N-dimethylformamide under nitrogen atmosphere was added 0.042 mL (0.24 mmol) of N,N-diisopropylethylamine and 37 mg (0.097 mmol) of 2-(1H-7-azabezotriazole-1-yl)-1,1,3,3,-tetramethyl uranium hexafluoro phosphate methanium. The resulting reaction mixture was stirred at ambient temperature overnight. The reaction was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to give 23 mg of the title compound. LC/MS: (M+1)=641.2.