Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:22].[H][H]>[Pd].C(O)C.CO.C(Cl)Cl>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1])[C:10](=[O:22])[CH2:11][CH2:12]2
Reactant: CN1CCCC1CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCCC1CCN1C(=O)CCc2cc(N)ccc21
Yield: 73 %

Procedure:
A suspension of 1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.25 g, 7.42 mmol) and palladium on activated carbon (10%, 100 mg, 0.09 mmol) in 50 mL ethanol was stirred under a balloon of hydrogen for 2 days. The suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL ethanol and the filtrate was concentrated to give a viscous oil. The crude product was subjected to Biotage flash chromatography on silica gel using 0-5% 2M NH3 in MeOH/CH2Cl2 to give a yellow foam (1.48 g, 72.9%). 1H-NMR (CDCl3) δ: 6.82 (d, J=8.4 Hz, 1H), 6.55 (dd, J=3.0, 8.4 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H), 4.09-3.99 (m, 1H), 3.86-3.76 (m, 1H), 3.54 (br s, 2H), 3.04-3.01 (m, 1H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.29 (s, 3H), 2.17-1.60 (m, 8H).
Reaction SMILES: BrC1N2C=NC=C2C(=O)N(CC2C=CC(OC)=CC=2)C=1.[CH:21]([N:34]1[C:38]2[CH:39]=[C:40](Br)[CH:41]=[CH:42][C:37]=2[O:36][C:35]1=[O:44])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC1C=CC(O)=C(B(O)O)C=1.[CH2:56]([O:63][C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][C:65]=1B(O)O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH:21]([N:34]1[C:38]2[CH:39]=[C:40]([C:69]3[CH:68]=[C:67]([CH3:70])[CH:66]=[CH:65][C:64]=3[O:63][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:41]=[CH:42][C:37]=2[O:36][C:35]1=[O:44])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(OCc2ccccc2)c(B(O)O)c1
Reactant: O=c1oc2ccc(Br)cc2n1C(c1ccccc1)c1ccccc1
Agent: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Agent: OB(O)c1cc(Cl)ccc1O
Product: Cc1ccc(OCc2ccccc2)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations to replace 5-bromo-7-(4-methoxybenzyl)imidazol[1,5-a]pyrazin-8(7H)-one with 3-benzhydryl-5-bromobenzo[d]oxazol-2(3H)-one and (5-chloro-2-hydroxyphenyl)boronic acid with (2-(benzyloxy)-5-methylphenyl)boronic acid, 3-benzhydryl-5-(2-(benzyloxy)-5-methylphenyl)benzo[d]oxazol-2(3H)-one was obtained as a colorless solid in quantitative yield (1.05 g): 1H NMR (300 MHz, CDCl3) δ7.30-7.16 (m, 17H), 6.98 (dd, J=8.3, 1.7 Hz, 1H), 6.80-6.76 (m, 3H), 6.68 (s, 1H), 4.95 (s, 2H), 2.24 (s, 3H); MS (ES+) m/z 497.8 (M+1).
Reaction SMILES: [CH3:1][N:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[N:7]([C:9]([CH3:12])=[N:10][N:11]=2)[N:8]=1.[C:22](Cl)(=[O:30])OC1C=CC=CC=1.[CH3:32][NH:33][CH3:34]>C(Cl)Cl.C1COCC1.O>[CH3:32][N:33]([CH3:34])[C:22]([NH:13][C:5]1[C:6]2[N:7]([C:9]([CH3:12])=[N:10][N:11]=2)[N:8]=[C:3]([N:2]([CH3:1])[C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:4]=1)=[O:30]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC
Reactant: Cc1nnc2c(N)cc(N(C)[C@@H](C)c3ccccc3)nn12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1nnc2c(NC(=O)N(C)C)cc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of compound (S)-N6, 3-dimethyl-N6-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (50 mg, 0.17 mmol) in DCM (10 mL) was added phenyl carbonochloridate (30 mg, 0.19 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then the solution of dimethylamine in THF (0.3 mL, 1 N) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EA (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated in vacuum. The residue was purified by prep-TLC (DCM: MeOH=20:1) to give product (S)-1,1-dimethyl-3-(3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)urea (Compound 8) as a yellow solid (10 mg, 16.7%). 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.80 (s, 1H), 7.34-7.32 (m, 5H), 3.12 (s, 6H), 2.80 (s, 3H), 2.65 (s, 3H), 1.60 (d, 3H); LRMS (M+H+) m/z: calcd 353.20; found 353.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:24]=[CH:23][C:22]2[NH:21][C:20]3[N:25]=[CH:26][C:27]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)=[CH:28][C:19]=3[C:18]=2[CH:17]=1>CN(C=O)C>[NH3:4].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:24]=[CH:23][C:22]2[NH:21][C:20]3[N:25]=[CH:26][C:27]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)=[CH:28][C:19]=3[C:18]=2[CH:17]=1
Reactant: CN(C)CCO
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnccc5Cl)cc4c3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccncc1-c1cc2c(cn1)[nH]c1ncc(-c3cnn(C)c3)cc12
Product: N
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 38 mg, 0.96 mmol) was added to a solution of N,N-dimethylethanolamine (63 mg, 0.71 mmol) in DMF (5 mL) and the mixture stirred at ambient temperature for 75 minutes. 6-(4-chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (85 mg, 0.24 mmol) was added and the reaction mixture was stirred at ambient temperature for 26 h then at 80° C. for 2 h. After this time, the reaction mixture was added to a solution of N,N-dimethylethanolamine (0.48 mL) and sodium hydride (60% dispersion in mineral oil, 288 mg) in DMF (2 mL), which had been pre-stirred for 15 minutes. The reaction mixture was stirred at 80° C. overnight before being poured onto water and the resultant solid collected by filtration. The material was purified by flash chromatography (silica, 12 g column, ISCO, 0-20% methanol in DCM then 20% (2N ammonia in methanol) in DCM) to afford the title compound as a yellow oil which crystallised on standing (0.1 g, 58%). 1H NMR (CD3OD, 400 MHz): 8.94 (d, J=1.1 Hz, 1H), 8.81-8.77 (m, 2H), 8.71 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.48 (d, J=5.9 Hz, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.28 (d, J=5.9 Hz, 1H), 4.42 (t, J=5.2 Hz, 2H), 3.98 (s, 3H), 3.03 (t, J=5.1 Hz, 2H), 2.42 (s, 6H). LCMS (Method A): RT=3.93 min, M+H+=414.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[CH3:13][NH:14][CH3:15].[CH2:16]=O.[OH-].[Na+]>O>[CH3:13][N:14]([CH3:16])[CH2:15][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: C=O
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 7-nitro-1H-indole (3 g, 18.5 mmol), 40% aqueous dimethylamine (3.12 mL, 27.7 mmol) and 37% aqueous formaldehyde (1.57 mL, 19.3 mmol) was stirred for three days at ambient temperature. The reaction mixture was diluted with H2O (20 mL) followed 15% aqueous NaOH (200 mL) and extracted with CHCl3 (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=181 (M+1).
Reaction SMILES: [N+:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)([O-:3])=[O:2].C(Cl)[Cl:19]>>[ClH:19].[N+:1]([O-:3])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(O[N+](=O)[O-])CC1
Product: Cl
Product: O=[N+]([O-])OC1CCNCC1

Procedure:
To a solution of tert-butyl 4-(nitrooxy)piperidine-1-carboxylate (2.10 g; 8.53 mmol) in DCM (15 mL) cooled to 0° C., HCl gas was bubbled for 2 hrs. The solvent was concentrated and the residue was treated with diethyl ether, affording the title compound which was used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13]O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.O=S(Cl)[Cl:24].C([O-])([O-])=O.[Na+].[Na+].[C:32]1([P:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl-:24].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][P+:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1ncc(-c2ccc(F)cc2)o1
Reactant: O=S(Cl)Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2cnc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)o2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-(4-fluorophenyl)-1,3-oxazol-2-yl]methanol (0.46 g, 2.4 mmol) was dissolved in DCM (5 ml), then Et3N (0.3 ml, 2.4 mmol) and SOCl2 (0.35 ml,4.7 mmol) were added. The reaction mixture was stirred for 1 hour at room temperature under nitrogen. The mixture was diluted with DCM (20 ml) and a saturated solution of Na2CO3 (20 ml) was added carefully. The organic layer was separated, washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to give a yellow oil. This oil (0.5 g, 2.38 mmol) was treated with an equimolar amount of triphenylphosphine as described for Intermediate A (Step 3) to give the title compound. δH (360 MHz, DMSO) 5.76 (2H, d, J 16.0), 7.29 (2H, t, J 7.0), 7.39-7.46 (2H, m), 7.61 (1H, s), 7.74-7.95 (15H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12](=[O:25])[C:11]([C:26]([O:28]CC)=O)=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1Cl)[NH2:35].FC1C=CC(N)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12](=[O:25])[C:11]([C:26]([NH2:35])=[O:28])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)c2cc(-c3ccncc3)ccc2c1=O
Agent: Nc1ccc(F)cc1
Product: NC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
The starting acid was prepared by hydrolysis of ethyl 1-(3,4-dichlorophenyl)-1,4-dihydro-4-oxo-7-(4- pyridinyl)-3-quinolinecarboxylate (tan solid, m.p. 238°-240 ° C. when recrystallized from toluene), in turn prepared according to the procedures of Example 1, parts (e) and (f), substituting 3,4-dichloroaniline for the 4-fluoroaniline of part (e).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=1>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: Cn1cncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nccc(Cl)c2s1
Yield: 79.4 %

Procedure:
Nitrogen was bubbled through a mixture of the tin derivative 6 (7.19 g, 15.7 mmol) and 5-bromo-1-methyl-1H-imidazole (2.02 g, 12.5 mmol) [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057, b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598, c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.] in toluene (20 mL) for 5 minutes. Pd(PPh3)4 (1.50 g, 1.30 mmol) was added and nitrogen was bubbled for additional 5 minutes. Finally, the mixture was refluxed under nitrogen overnight, the resultant yellow suspension was concentrated under reduced pressure and then purified with flash chromatography (eluent EtOAc/MeOH 90:10), to afford title compound 16 as a yellow solid (2.48 g, 79% yield). MS (m/z): 250.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH:24]([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CI.[Li+].[CH3:32][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:32])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C#N)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile (0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at −78° C. was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution in THF. The resulting mixture was stirred overnight, with the temperature slowly rising to ambient. The reaction mixture was quenched with brine (1 mL), diluted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.255 g (74%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile. LC-MS Method 1 tR=1.89 min, m/z 459, 461 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83 (d, J=8.2 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 3.02-2.97 (m, 1H), 2.42-2.36 (m, 1H), 2.29-2.08 (m, 4H), 1.42 (d, J=7.0 Hz, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −116.50 (m).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.[Mg].CI.Cl[Ti:24](Cl)(Cl)Cl>C1COCC1>[CH:5]1[C:14](=[CH2:1])[CH:13]=[CH:12][CH:7]=1.[CH:16]1([Ti:24][CH:7]2[CH:12]=[CH:13][CH:14]=[CH:5]2)[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C1=CCC=C1
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: C1=CC([Ti]C2C=CC=C2)C=C1
Product: C=C1C=CC=C1
Temperature: 69 °C
Yield: 1863.7 %

Procedure:
Following the procedure of Example 1, 1.1 g (6.2 mMoles) of anthracene and 42.7 g of cyclopentadiene are added to 10.94 g (450 mMoles) of fine magnesium powder in 300 ml of THF, followed by activation with 0.1 ml of methyliodide and by treatment for 3 hours in an ultrasonic bath. 56.9 g (33 ml=300 mMoles) of TiCl4 are then added dropwise, which initiates an extremely vigorous reaction and an increase in temperature to 69° C. After the addition, the mixture is allowed to cool to 23° C. and 14.8 g of a scarlet-red compound are obtained after 12 hours, being isolated by filtration. Another 69.1 g are obtained from the filtrate by concentration. Total yield: 83.9 g of C5H4 --C5H4Ti2 (C5H5)2Cl2 corresponding to 179.9 mMoles=66% of the theoretical.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([N:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([O-:24])=[O:19].[CH3:16][N:15]([CH3:17])[C@H:10]1[C@H:11]([O:13][CH3:14])[CH2:12][NH2+:8][CH2:9]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1C[NH2+]C[C@H]1N(C)C
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic (trans)-tert-butyl-3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (0.68 g, 2.8 mmol) in DCM (4.0 mL) was added TFA (2.1 mL, 28 mmol), and the reaction mixture was stirred at room temperature for 18 h. Then, the reaction mixture was concentrated under reduced pressure to provide racemic (trans)-3-(dimethylamino)-4-methoxypyrrolidin-1-ium 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 4.42-4.48 (m, 1 H), 3.96-4.05 (m, 2 H), 3.60 (d, J=5.4 Hz, 2 H), 3.48-3.55 (m, 1 H), 3.39 (s, 3 H), 2.97 (s, 6 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[Mg].BrC(Br)C.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH3:33][NH2:34].Cl>C1COCC1.CO.O>[CH3:33][NH:34][C:27](=[O:31])[C:28]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:29]
Reactant: CN
Reactant: O=C(Cl)C(=O)Cl
Reactant: Brc1ccccc1COc1ccc(-c2ccccc2)cc1
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a stream of argon gas, 1-bromo-2-(biphenyl-4-yloxymethyl)benzene (33.92 g, 0.1 mol) in dry THF (140 ml) was dropwise added to a mixture of magnesium (4.86 g, 0.2 mol) and dibromoethane (0.2 ml) in dry THF (20 ml) at 50° to 60° C. over 40 minutes. The reaction mixture was stirred at 65° C. for 1 hour, diluted with dry THF (90 ml) and cooled below 20° C. This mixture was dropwise added to a solution of oxalyl chloride (15.23 g, 0.12 mol) in dry THF (250 ml) at -50° C. over 15 minutes, followed by stirring at -75° C. for 1 hour, and a 40% solution (46.59 g) of methylamine (0.6 mol) in methanol was added thereto at -20° C., followed by stirring at room temperature for 1 hour. After completion of the reaction, water (1000 ml) was added to the reaction mixture which was then adjusted to below pH 2 by addition of conc. HCl and extracted with ethyl acetate (600 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-oxoacetamide (24.52.g; yield, 71.0%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
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+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOC(=O)c1cncc(-c2ccc(OC)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
22.26 g (96.78 mmol) of ethyl 5-bromonicotinate, 25.00 g (164.5 mmol) of 4-methoxyphenylboronic acid, 0.56 g (0.48 mmol) of tetrakis(triphenylphosphine)palladium(0) and 20.51 g (193.6 mmol) of sodium carbonate were dissolved in a mixture of 180 ml of 1,2-dimethoxyethane, 50 ml of water and 400 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by flash chromatography (dichloromethane/acetonitrile 100:2<100:5). Yield: 20.18 g (72% of theory)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:21])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][C:15]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(I)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
Methyl 2-(2-(4-iodophenyl)acetamido)-4-methylthiophene-3-carboxylate (420.4 mg, 1.01 mmol), 4-pyridylboronic acid (Aldrich, 167 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol), and potassium carbonate (565 mg, 4.1 mmol) were combined in DME (2 mL) and water (1 mL) in a sealed tube, and heated to 80° C. over 17 h. The reaction mixture was cooled to rt, then partitioned between EtOAc and water. The organic layer was separated, washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography (EtOAc/hexanes) afforded the titled compound. 1H NMR (CDCl3) δ11.3 (s, 1H), 8.67 (dd, J=4.7, 1.4H, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.60-7.40 (m, 4H), 6.38 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ167.7, 166.6, 150.3, 149.9, 147.8, 137.4, 134.8, 134.6, 130.3, 127.7, 121.5, 113.0, 112.3, 51.5, 43.5, 17.8; MH+ 367.1.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Br:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:9][C:6]1[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1cccs1
Solvent: CN(C)C=O
Product: CCCc1ccc(Br)s1
Yield: 89.3 %

Procedure:
A solution of 2-propylthiophene (1.00 g, 7.92 mmol) and N-bromosuccinimide (1.55 mg, 8.71 mmol) in N,N-Dimethylformamide (60 mL) was heated at 65° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in cyclohexane (20 mL) and successively washed with a 5% sodium thiosulfate solution (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-bromo-5-propylthiophene (11a) (1.45 g, 7.07 mmol, 89%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]2[C:13](=[O:27])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([C:18]([F:21])([F:20])[F:19])[NH:16][CH:17]=2)=[C:4]([F:28])[CH:3]=1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([C:12]2[C:13](=[O:27])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([C:18]([F:21])([F:19])[F:20])[N:16]([CH3:31])[CH:17]=2)=[C:4]([F:28])[CH:3]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)[nH]cc(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)n(C)cc(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.9 %

Procedure:
20 g (47 mol) of 5-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3-ethoxycarbonyl-2-trifluoromethyl-4(1H)-pyridone was dissolved in 150 ml of DMF, and 2.1 g (53 mmol) of 60% sodium hydride was added thereto under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 14 g (99 mmol) of methyl iodide was added thereto. After stirring at room temperature for 8 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 6 g (yield: 28%) of the desired product. Melting point: 170-172° C.