Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:26][CH2:25]2)[CH:16]=1
Reactant: c1cncc(CCCN2CCNCC2)c1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a mixture solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 1.7 g, 1-[3-(3-pyridyl)propyl]piperazine 1.56 g, 1-hydroxy-benzotriazole 1.3 g and N,N-dimethylformamide 20 ml was added dicyclohexylcarbodiimide 1.67 g under ice-cooling, and the mixture stirred overnight at room temperature. Ethyl acetate 50 ml was added, the precipitated dicyclohexylurea filtered off, water 30 ml added to the filtrate, the resultant solution basified with sodium hydrogen, carbonate and transferred into a separating funnel. The aqueous layer was washed with ethyl acetate, the washings combined with the ethyl acetate layer, and the resultant ethyl acetate solution washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate methanol (4:1) to give 860 mg of oily 1-[3-(3-pyridyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. This product was dissolved in ethanol 8 ml and after addition of fumaric acid 250 mg, the mixture allowed to stand to yield crystals. The crystals were filtered off and dried to give 580 mg of 1-]3-(3-pyridyl)propyl-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. fumarate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:7])=[CH:4][CH:3]=1.[CH3:15][Mg]I.Cl>C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([C:11]#[N:12])[C:9]#[N:10])([CH3:15])[CH3:7])=[CH:13][CH:14]=1
Reactant: CC(=C(C#N)C#N)c1ccc(Cl)cc1
Reactant: C[Mg]I
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Product: CC(C)(c1ccc(Cl)cc1)C(C#N)C#N
Yield: 69 %

Procedure:
First, 1.00 g of (4-chloro-α-methylbenzylidene)malononitrile of the formula: was dissolved in 20 ml of diethyl ether, to which a catalytic amount of copper (I) iodide was added, and while stirring under ice cooling, a solution of methyl magnesium iodide in diethyl ether (prepared from 0.30 g of magnesium, 10 ml of diethyl ether, and 0.86 ml of methyl iodide) was added dropwise, followed by stirring for 30 minutes under ice cooling. Then, 10% hydrochloric acid was added to the reaction mixture, which was extracted with ethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.74 g of (1-(4-chlorophenyl)-1-methylethyl)malononitrile (the intermediate (2)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[C:8]1[CH2:14][N:13]2[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:6]#[N:7])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:8]1[CH2:14][N:13]2[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:6]#[N:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CN2CCCC1C2

Procedure:
A solution of ethyl(1-azabicyclo[3.2.1]octan-6-ylidene)cyanoacetate (41 g, 0.19 mol) in abs. ethanol (500 ml) was treated with 10% palladium on carbon (5 g) and hydrogen in a Parr shaker at 30 psi for 5 h. Filtration and evaporation gave the title compound in 36 g yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:38]([Mg]Br)=[CH2:39].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH:38]=[CH2:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of 6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.25 g, 0.46 mmol) in THF (10 mL) was cooled to 0° and treated with vinylmagnesium bromide (1 M in THF, 1.02 mL). The reaction mixture was allowed to warm to rt as the bath melted. After 5 h, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (188 mg, 72%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.71 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.04-5.11 (m, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.09-2.19 (m, 1H), 0.76-1.07 (m, 3H), 0.39-0.54 (m, 1H). LCMS (m/z, ES+)=569 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][N:19]3[C:23]([C:24](OC)=[O:25])=[N:22][CH:21]=[N:20]3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:24]([C:23]1[N:19]([CH2:18][C:8]2[N:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:20]=[CH:21][N:22]=1)=[O:25]
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Methyl 1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate was treated with excess methylamine in methanol in a sealed tube at 80° C. for several hours until the reaction was completed as judged by TLC or LC analysis. Solvent was evaporated and the crude product was purified by chromatography (SiO2 column, eluted with 50% acetone). m/e+ 361 for C20H21N6O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.13 (d, J=0.6 Hz, 1H), 7.87 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.08 (dd, J=1.2, 9.3 Hz, 1H), 6.32 (s, 2H), 3.06 (d, J=5.1 Hz, 3H), 2.50 (bs, 1H), 2.41 (s, 3H), 2.31 (s, 3H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.440, 150.38, 146.788, 146.587, 138.174, 131.289, 129.586, 129.413, 128.819, 128.612, 122.655, 122.094, 117.100, 113.447, 44.395, 26.393, 21.605, 18.714 ppm.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:37]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:37].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1
Agent: Cl
Product: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-benzhydryloxy]azetidine (132) (3.8 mmol) using the procedure described for compound (9) (0.70 g, 60%).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][CH:8]([O:16][CH3:17])[CH2:9][CH:10]1[S:15][CH2:14][CH2:13][CH2:12][S:11]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=2)[CH:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH3:30])=[C:26]([CH2:28][C:10]3([CH2:9][CH:8]([O:7][CH3:6])[O:16][CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]3)[N:27]=2)[CH:24]=1
Reactant: Cc1c(CCl)nc2ccc(Cl)cn12
Reactant: COC(CC1SCCCS1)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CC1(Cc2nc3ccc(Cl)cn3c2C)SCCCS1)OC
Temperature: -30 °C

Procedure:
A solution of n-BuLi in hexanes (1.6 M, 1.4 mL) is added dropwise at −50° C. to a solution of 2-(2,2-dimethoxy-ethyl)-[1,3]dithiane (450 mg, prepared according J. Het. Chem, 1987, 1221) in THF. The mixture is then warmed to −30° C. for 1 hour. After cooling to −50° C., a solution of 6-chloro-2-chloromethyl-3-methyl-imidazo[1,2-a]pyridine (300 mg) in 3 mL of THF is added dropwise; the reaction mixture is then slowly warmed to room temperature. After quenching with aqueous NH4Cl solution, the mixture is extracted with ethyl acetate. The extract is washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue is purified on flash chromatographic column, eluting with 5% MeOH in CH2Cl2, to give 6-Chloro-2-[2-(2,2-dimethoxy-ethyl)-[1,3]dithian-2-ylmethyl]-3-methyl-imidazo[1,2-a]pyridine. 1H NMR (CDCl3, ppm): 7.80 (s, 1H); 7.50(d, 1H); 7.05(d, 1H); 4.80(t, 1H); 3.40(m, 8H); 2.75-3.00(m, 4H); 2.40-2.50(m, 5H); 1.80-2.05(m, 2H). Step 2. Preparation of 6-Chloro-2-[2-(6-fluoro-pyridin-2-yl)-2H-pyrazol-3-ylmethyl]-3-methyl-imidazol[1,2-a]pyridine
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([B:26]([OH:29])[OH:27])=[CH:15][C:14]=1[CH3:20])[CH2:11][F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(B(O)O)ccc1[C@@H](CF)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To a solution of 24B (0.46 g, 1.364 mmol) in THF (7 mL) at −78° C., was added a solution of n-BuLi (2.2 mL, 3.52 mmol) dropwise. The mixture was stirred at −78° C. for 15 min, then was treated with trimethyl borate (0.456 mL, 4.09 mmol). The reaction was stirred at −78° C. for 15 min, then was allowed to warm to rt and stir for 3 h. The reaction mixture was diluted with EtOAc (30 mL), treated with 1N HCl (20 mL). The mixture was stirred at rt for 1 h. The phases were separated, then the aqueous layer was extracted with EtOAc. The combined organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc/hexanes) to give 24C (0.2 g, 0.662 mmol, 48.5% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.97-8.10 (m, 2H) 7.28-7.44 (m, 6H) 4.82 (d, J=5.56 Hz, 1H) 4.71 (d, J=5.56 Hz, 1H) 4.53-4.59 (m, 2H) 3.56-3.90 (m, 3H) 2.47 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −223.99 (s, 1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:31][CH:32]=2)=[O:27])[CH2:22]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57.8 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: Fc1ccc(Br)c(I)c1
Product: COc1ccc(Sc2cc(F)ccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCCCBr
Product: ClCCCOc1cccc(Br)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-bromophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[C@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 10 %

Procedure:
Prepared in analogy to example 1 (b) from 2-((R)-sec-butoxy)-5-methanesulfonyl-benzoic acid (Example A20) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 10%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH2:9]>>[CH3:8][NH:9][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7]
Reactant: CN
Reactant: C1CCC2OC2C1
Product: CNC1CCCCC1O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Cyclohexene oxide (147 g, 1.5 mol) was dissolved in a ethanolic 8 M methylamine solution (750 ml) and stirred at 40° C. for 16 h. The reaction mixture was concentrated in vacuo to give racemic 2-methylaminocyclohexanol as a slightly brown oil (195 g, 100%). According to GC-analysis this product was 99+% pure and used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:33]=[CH:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:30]=2)O1>>[C:37]([O:36][C:34]([N:31]1[CH:32]=[CH:33][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccn(C(=O)OC(C)(C)C)c3)ccn2c1=O
Yield: 62 %

Procedure:
Methyl 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (151.0 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (89 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1Br
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Yield: 62 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-4-methylbenzoic acid (400 mg) and 3-(trifluoromethyl)aniline were converted to the title compound (410 mg, 62%)
Reaction SMILES: [Na].[C:2]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14])([CH3:4])=[CH2:3].[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2NC1=O)([CH3:17])=C.[H-].[Na+].O1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[NH:18]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:32]2[CH2:33][CH2:34][N:5]([CH2:9][CH2:8][CH2:13][N:7]3[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[N:5]([C:2]([CH3:4])=[CH2:3])[C:6]3=[O:14])[CH2:2][CH2:31]2)=[CH:15]1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 gm of the above intermediate were dissolved in 5 ml tetrahydrofuran and added to a cooled suspension of N-isopropenyl-benzimidazolone sodium salt prepared from 0.34 gm of N-isopropenyl-benzimidazolone and 0.05 gm of sodium hydride in 5 ml of dimethylformamide. The mixture was stirred for 16 hours at room temperature and then poured on ice-water-ammonia. The crystalline product was filtered off and dried. Yield: 0.65 gm (81% of theory), m.p. 68° C., identical with the product obtained by method B in Example 6.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][N:18]([CH2:30][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CCc3ccc(Cl)cc3)Cc3ccc(C(=O)OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of {4-[(4-butylphenyl)ethynyl]benzyl}[2-(4-chlorophenyl)ethyl]amine (2.85 g, 7.1 mmol) and methyl 4-formylbenzoate (1.16 g, 7.1 mmol) in DCE (24 mL) was added at once sodium triacetoxyborohydride (2.25 g, 10.6 mmol) and the resulting reaction mixture was stirred 12 hrs at rt. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex (5/95)) gave 2.8 g (73%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.98 (d, J=8.3 Hz, 2H), 7.51-7.43. (m, 4H), 7.36 (d, J=8.3 Hz, 2H), 7.29-7.15 (m, 6H), 7.00 (d, J=8.3 Hz, 2H), 3.94 (s, 3H), 3.68 (s, 2H), 3.64 (s, 2H), 2.83-2.59 (m, 6H), 1.69-1.55 (m, 2H), 1.44-1.30 (m, 2H), 0.95 (J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[SH:43][CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:66])[F:65])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)=[O:46]>C(Cl)Cl>[O:46]=[C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:65])[F:66])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)[CH2:44][S:43][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(CS)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CSC(=O)c1ccccn1)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
Picolinic acid (0.25 g, 2.04 mmol) was dissolved in anhydrous, degassed DCM (5 ml), HATU (775 mg, 2.04 mmol) was added followed by DIEA (0.53 g, 4.1 mmol). The mixture was stirred for 20 min and N-[4-(2-Mercapto-acetyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide SII-4 (0.725 g, 1.85 mmol) was added in 5 ml anhydrous, degassed DCM and the mixture was stirred for 16 hours. The reaction was filtered and the solvent evaporated. The product was purified by flash chromatography (1:1 EtOAc:hexanes) to afford 125 mg (0.25 mmol, 14%) product as a white solid. 1H-NMR: (400 MHz, DMSO): 11.12 (s, 1H), 8.89 (d, 1H), 8.03 (t, 1H), 8.01 (d, 2H), 8.00 (d, 2H), 7.90 (d, 1H), 7.78 (t, 1H), 7.60 (d, 2H), 7.14 (d, 2H), 4.60 (s, 2H); LC-MS (ES+): 497 [MH]+ m/e.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[OH-].[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23]>>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])[CH2:4][CH:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O
Yield: 97 %

Procedure:
A mixture of the N,N-dimethyl-2,6-di-t-butyl-4-aminomethylphenol (10.5 g, 40 mmols), sodium hydroxide (1.8 g, 45 mmols) and acetylacetone (24 mLs, 10% solution) was refluxed for 3 hours. Acetylacetone was distilled under reduced pressure to afford an oily residue of the 3-(3',5'-di-t-butyl-4'-hydroxybenzyl)-2,4-pentanedione compound (97% by VPC).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][CH2:10][C:11]([O:13][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To mixture of Boc-β-alanine (N-Boc-β-Ala-OH; 1 g, 5.29 mmol) and N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added 1-hydroxybenzotriazole hydrate (HOBt.xH2O; 0.7 g, 5.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (3×100 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as a white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (br s, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H).