Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Br:14][CH2:15]Br.C([Li])CCC.CS(O)(=O)=O.OC(C(O)(C)C)(C)C>O1CCCC1>[Br:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: BrCBr
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(CBr)OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
To a mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 mL, 120 mmol), and tetrahydrofuran (150 mL) was added dropwise n-butyl lithium (2.6 M n-hexane solution, 39 mL, 100 mmol) over a period of 1.5 hours at −78° C., and then the reaction mixture was stirred for 1.5 hours at the same temperature. This mixture was then stirred for 2 hours at room temperature, after which it was cooled to 0° C., methanesulfonic acid (6.5 mL, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred for 1 hour at room temperature. The mixture was cooled to 0° C., pinacol (12 g, 100 mmol) was added to the reaction mixture, and the reaction mixture was then stirred for 1 hour at room temperature. The reaction mixture was concentrated under a reduced pressure, after which the residue thus obtained was distilled under a reduced pressure (74-76° C., 8 mmHg) to obtain the title compound (16 g, 68%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[I-:10]>ClC1C=CC=CC=1>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [I-]
Reactant: CCCCCCCCBr
Solvent: Clc1ccccc1
Product: CCCCCCCCI

Procedure:
A reaction using the above reactor was conducted using the following chemistry. Bromooctane in the organic solvent chlorobenzene was reacted with aqueous iodide to form iodoctane in chlorobenzene and aqueous bromide ion. To ensure that this reaction required the use of a phase transfer catalyst, a brief dispersed-phase study was conducted. A solution 0.5 M in bromooctane and 0.1 M in tetradecane (as a gas chromatograph standard) in chlorobenzene was stirred with an equal volume of 2.0 M potassium iodide at 40 degrees C. for 4 hours. After this period, no iodooctane could be detected by gas chromatography. All analyses were conducted with a Perkin-Elmer 3920 gas chromatograph equipped with a flame ionization detector and a 10' by 1/8" OV-101 column at 200 degrees C. When this experiment was repeated using 0.05 M tetrabutylammonium bromide in the organic feed as a phase transfer catalyst, 50% conversion of bromooctane to iodoctane was observed after 4 hours. Because the organic-phase concentration of tetrabutylammonium iodide, the active form of the catalyst, remains constant with time under these reaction conditions, first-order kinetics with respect to the disappearance of bromooctane is predicted by the phase transfer catalysis mechanism. This effect was observed in these experiments.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[C:26]([C:25]1[CH:24]=[C:23]2[C:22](=[CH:21][CH:20]=1)[C:32](=[O:31])[N:1]([C:2]1[CH:3]=[C:4]([C:8]3[O:9][C:10]4[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:5]=[CH:6][CH:7]=1)[C:29]2=[O:30])([OH:28])=[O:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(-c2nc3cccc(C(=O)O)c3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cccc(C(=O)O)c4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-7-carboxylic acid (100 mg, 0.39 mmol) and 1,2,4-benzenetricarboxylic anhydride (75 mg, 0.39 mmol) the title compound was obtained, (148 mg, 32%). 1H NMR (DMSO) δ 8.50(m, 2H), 8.39(m, 2H), 8.17(m, 2H), 8.01(m, 1H), 7.88(m, 2H), 7.63(t, 1H). MS 429 m/z (M+H)+.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)CCC>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:2]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccccc2)c1

Procedure:
[1,1′-biphenyl]-3-amine (8.49 g, 50.2 mmol), 2-chloro-3-nitropyridine (7.23 g, 45.6 mmol), triethylamine (6.99 mL, 50.2 mmol), and 200 mL of butanol were added to a 1 L round bottom flask. The mixture was refluxed overnight under nitrogen. The next day the solvent was evaporated, and the residue was taken up in dichloromethane and washed twice with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated leaving an orange oil. 14.61 g, assume quantitative yield (13.29 g).
Reaction SMILES: [CH3:1][N:2]([CH2:34][C:35]#[CH:36])[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14](CC2C=CC=CC=2)[CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[ClH:37]>CC(O)C.[Pd].ClCCl.CCOCC>[ClH:37].[CH3:1][N:2]([CH2:34][C:35]#[CH:36])[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1
Reactant: C#CCN(C)C(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: ClCCl
Product: C#CCN(C)C(=O)COc1ccc(CCNCC(O)COc2ccccc2)cc1

Procedure:
A solution of N-methy-N-propargyl 4-[2-(N-benzyl-N-(2-hydroxy-3phenoxypropyl)amino)ethyl]phenoxyacetamide (1.0 g) was dissolved in propan-2-ol (70 ml). 10% Palladium on carbon catalyst (0.2 g) was added and the mixture hydrogenated overnight under an atmosphere of hydrogen. The catalyst was separated by filtration through Keiselguhr and the filtrate evaporated under reduced pressure to give an oil. This residue was dissolved in dichloromethane (70 ml) and the pH (as indicated on moist test paper) was adjusted to 3 by adding a saturated solution of HCl in ether. The solvent was evaporated and this process was repeated as described in Example 26. The final residual oil (0.9 g) was suspended in a minimum amount of propan-2-ol from which it crystallised. A small amount of methyl acetate was added before the solid was filtered off and air-dried to give N-methyl-N-propargyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]-phenoxyacetamide hydrochloride salt (0.3 g) mp 105°-107° C.. NMR: 0.73-0.92[m,3 H, hindered rotamers CH2CH3 ]; 1.35-1.67[m,2H, hindered rotamers, NCH2CH2CH3 ]; 2.80 and 2.96[pr.s,3H, hindered rotamers, N-CH3 ]; 2.84-3.02[m,2H,CHHD 2C6H4 ]; 3.02-3.30[m,4H,CH2NHCHHD 2]; 3.98[m,2H, OCH2CHOH]; 4.20[m,1H,CHOH]; 4.74[s,2H,OCH2CO]; 6.80-6.98[m,5H, aromatic H]; 7.10-7.34[m,4H, aromatic H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28](O)=[O:29])=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[Cl:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][C:65]=1[F:66])[NH2:62]>CC#N>[Cl:58][C:59]1[CH:60]=[C:61]([NH:62][C:28]([C:26]2[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:38])[F:39])[CH2:33][CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([CH3:13])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:29])[CH:63]=[CH:64][C:65]=1[F:66]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2-fluoro-2-methyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (60 mg, 0.100 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (33 mg, 0.25 mmol), DIPEA (86 μL, 0.50 mmol) and MeCN (2 mL) is stirred for 20 min. This mixture is added to 3-chloro-4-fluoro-aniline (0.200 mmol) and it is stirred overnight at rt. The mixture is directly purified via reverse phase HPLC. Yield: 39 mg. HPLC Rt=0.607 min (method F). MS m/z: 731 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[N+:25]([O-])=O)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[NH2:25]
Reactant: O=C(C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CCC(=O)N2CCCCC2)ccc1O
Reaction time: 1 h
Yield: 103.3 %

Procedure:
0.5 g of N-(4-benzyloxy-3-nitrocinnamoyl)piperidine (prepared as described in Example 12) was dissolved in 30 ml of methanol. 300 mg of 10% palladium-on-carbon were added to the solution, which was then catalytically reduced whilst bubbling hydrogen through it, under atmospheric pressure for 60 minutes. The catalyst was then removed by filtration, and the methanol was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to afford 0.35 g of the title compound as crystals, melting at 149°-150° C.
Reaction SMILES: C([Mg]Cl)C1C=CC=CC=1.O1CCCC1.[C:15]([O:19][C:20](=[O:54])[NH:21][C:22]1[S:23][C:24]([CH:45]([OH:53])CC2C=CC=CC=2)=[CH:25][C:26]=1[S:27](=[O:44])(=[O:43])[N:28]([CH2:30][CH:31]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[O:32][CH2:33][O:34][CH3:35])[CH3:29])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:54])[NH:21][C:22]1[S:23][C:24]([CH:45]=[O:53])=[CH:25][C:26]=1[S:27](=[O:44])(=[O:43])[N:28]([CH2:30][CH:31]([C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[O:32][CH2:33][O:34][CH3:35])[CH3:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: COCOC(CN(C)S(=O)(=O)c1cc(C(O)Cc2ccccc2)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COCOC(CN(C)S(=O)(=O)c1cc(C=O)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1

Procedure:
From (3-{[2-(4-fluorophenyl)-2-methoxymethoxyethyl]methylsulfamoyl}-5-formylthiophene-2-yl)carbamic acid t-butyl ester (160 mg) and 0.35 mL of a solution (0.35 mL) of 2.0M benzyl magnesium chloride-tetrahydrofuran, [3-{[2-(4-fluorophenyl)-2-methoxymethoxyethyl]methylsulfamoyl}-5-(1-hydroxy-2-phenylethyl)thiophene-2-yl]carbamic acid t-butyl ester was obtained, in the same way as Preparation Example 87. Thereafter, oxidation reaction was carried out, which was the same as Preparation Example 108, and the title compound (47 mg) was obtained as an orange oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OC(C)=C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[C:10]([OH:12])=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc(F)c2c1CCCC2=O
Agent: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Product: COc1ccc(F)c2c(O)cccc12

Procedure:
8-Fluoro-5-methoxy-l-tetralone (20 g) was dissolved in isopropenyl acetate (70 ml), p-toluenesulphonic acid (1 g) was added and the mixture was heated under reflux under nitrogen for 5 days. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution (250 ml) and the crude product extracted into ethyl acetate (3×100 ml). The combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed under reduced pressure. The resulting dark oil was taken up into dioxan (200 ml) and dichlorodicyanobenzoquinone (DDQ) (25 g) was added. The solution was heated under reflux for 18 hours and filtered to remove DDQ residues. The solvent was removed under reduced pressure and the crude product purified by chromatography on silica (eluent hexane/ethyl acetate 3:1). The resulting red oil was dissolved in methanol (100 ml) and heated under reflux with sodium hydroxide (9 g) for 1 hour. Water (100 ml) was added and the mixture was washed with ether/hexane 1:1 (200 ml). The aqueous phase was acidified and the product collected by filtration to give a dark solid after drying.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (4.0 g, 20.3 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (893 mg, 22.33 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Next, p-toluensulfonyl chloride (4.64 g, 24.26 mmol) was added, and the reaction mixture was stirred for 1 hour while warming to RT. The reaction mixture was subsequently diluted with DCM (300 mL) and washed with brine. The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (1% to 2% MeOH/DCM) to give the title compound as a white solid (6.87 g, 96%). 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (d, 1H, J=2.0 Hz), 8.43 (d, 1H, J=2.0 Hz), 7.74-7.78 (m, 3H), 7.29 (d, 2H, J=8.0 Hz), 6.83 (d, 1H, J=4.0 Hz), 2.38 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C14H11BrN2O2S, 351, 353; found 351, 353.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH3:34])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH3:34])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1OCC
Temperature: 70 °C
Yield: 86.3 %

Procedure:
tert-Butyl 2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (173.1 mg) was taken up in dioxane (4 mL) and 1.0 M aqueous LiOH (1.11 mL) was added. The reaction was stirred at 70° C. 16 h, and stirred at 80° C. for an additional 5 h. The mixture was cooled to room temperature and poured into a separatory funnel containing EtOAc and 1.0 M HCl. The water layer was removed and the EtOAc layer was washed with water. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give title compound (131.4 mg). LCMS m/z=410.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.28-1.34 (m, 6H), 2.15-2.26 (m, 1H), 2.54 (dd, J=16.3, 7.9 Hz, 1H), 2.68 (dd, J=16.3, 6.7 Hz, 1H), 2.72-2.82 (m, 1H), 3.53-3.62 (m, 1H), 3.91-4.93 (m, 6H), 4.95 (s, 2H), 6.0 (s, 1H), 6.73 (dd, J=8.7, 2.4 Hz, 1H), 6.90-6.96 (m, 2H), 7.02-7.06 (m, 2H), 7.17 (d, J=9.0 Hz, 1H), 12.3 (bs, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]([F:18])([F:17])[C@H:14]([OH:16])[CH3:15]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:16][C@H:14]([CH3:15])[C:13]([F:18])([F:17])[F:12])[CH:7]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: C[C@@H](Oc1cc(F)ccc1N)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-1,1,1-trifluoropropan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:29][CH:30]=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC#N
Product: O=CC=Cc1cccc(Cl)c1
Yield: 59.4 %

Procedure:
A solution of 3.00 g of 3-chlorobenzaldehyde and 6.49 g of (triphenylphosphoranylidene)acetaldehyde in 100 ml of acetonitrile was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.11 g (yield 59%) of 3-(3-chlorophenyl)-2-propenal as a solid.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.[Cl-].[NH4+]>CN(C)C=O>[CH:24]1([CH2:23][O:1][C:2]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:26][CH2:25]1
Reactant: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C1(OCC2CC2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
3 g (11.4 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate in 20 ml of N,N-dimethylformamide are added dropwise to a suspension of 1.4 g of sodium hydride at 60% in oil (34.2 mmol) in 14 ml of N,N-dimethylformamide, precooled to 0° C. After stirring for 20 minutes, 1 ml of bromomethylcyclopropane (11.4 mmol) is added and stirring is continued for 1 hour 30 minutes. The reaction medium is hydrolysed with saturated aqueous ammonium chloride solution and then extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. 4 g of crude residue are obtained and are purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 95/5 to 80/20. 2.9 g (81%) of tert-butyl 3-cyclopropylmethoxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19](Cl)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[CH:10]([C:19](=[O:20])[C:15]3[S:16][CH:17]=[CH:18][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CN(Cc2ccccc2)CCC1c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2sccc2C2CCN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 12 %

Procedure:
A solution of the product from step e) (4.38 g, 12.3 mmol) in CH2Cl2 (18.5 ml) was added dropwise to a slurry of AlCl3 (4.91 g, 36.9 mmol) in CH2Cl2 (42 ml) at 22° C. After 45 minutes, the reaction mixture was poured into ice cold 2 M NaOH (100 ml) and extracted with CH2Cl2 (300 ml). The organic extract was dried (MgSO4) and purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give the subtitle product (434 mg, 12%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[C@H:10]([CH3:18])[CH2:9]1)(OC(C)(C)C)=O.[ClH:19]>O1CCOCC1>[ClH:19].[CH3:18][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]([NH2:17])=[O:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1CC(N)=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
A mixture of (R)-2-(4-Boc-2-methylpiperazin-1-yl)acetamide (114 mg, 0.44 mmol) and 5N hydrochloric acid (0.2 ml) in 1,4-dioxane (2.0 ml) was stirred at 90° C. for 20 min. The mixture was concentrated in vacuo to afford (R)-2-(2-methylpiperazin-1-yl)acetamide hydrochloride salt quantitatively.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[CH3:7].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][C:3]1[C:2]([NH:1][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[C:6]([CH3:7])[N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1nn(-c2ccccc2)c(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(-c2ccccc2)c(C)c1NCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 38.1 g. 4-amino-3,5-dimethyl-1-phenylpyrazole, 77.5 g. N-(2-bromoethyl)-phthalimide and 42 g. potassium carbonate in 600 ml. acetonitrile is boiled for 15 hours, with stirring. After cooling, insoluble material is filtered off with suction and the filtrate is evaporated. The residue is stirred with methylene chloride and suction filtered and the filtrate is purified on a silica gel column using, as elution agents, first methylene chloride and then methylene chloride-ethyl acetate (6:4 v/v). There are obtained 41 g. (56% of theory) of a brownish oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:32][CH2:33][CH:34]2[CH2:38][CH:37]=[CH:36][CH2:35]2)(=O)=O)=CC=CC=1>>[CH:34]1([CH2:33][CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:38][CH:37]=[CH:36][CH2:35]1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CC=CC1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CCC2CC=CC2)c1
Yield: 36.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent-3-en-1-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (140 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCC2CC2)s1
Yield: 50 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (39 mg, 50%) which was obtained as a white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[N:7]=[C:6]([C:8]([NH:10][C:11]4[O:12][C:13]([C:16]5[O:17][CH:18]=[CH:19][CH:20]=5)=[N:14][N:15]=4)=[O:9])[CH:5]=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(Br)n1
Product: CCc1ccc(-c2ccc(-c3cccc(C(=O)Nc4nnc(-c5ccco5)o4)n3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 6-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-pyridinecarboxamide prepared in Reference Example 11 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.