Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1Cl
Yield: 14.7 %

Procedure:
As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.315 g (1.8 mmol) of 2-chlorobenzoyl chloride in dichloromethane. The product is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give a solid. Recrystallization from hexane-dichloromethane gives 100 mg of crystals, m.p. 110°-115° C. Anal. Calc'd for C28H21ClN2 O2 1/2 H2O: C,72.8; H,4,8; N,6.1; Cl,7.7. Found: C,72.6; H,4.5; N,5.8; Cl,8.7.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[N:22]1([C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (200 mg), pyrrolidine (65 μL), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (210 mg, yield 90%) as pale-yellow needle crystals. melting point 248-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]Br>C(OCC)(=O)C>[Br:13][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:12]
Reactant: O=C1CCCc2cc(Cl)ccc21
Reactant: BrBr
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Cl)cc2CCC1Br

Procedure:
5 g of 6-chloro-1-tetralone are reacted with 4.4 g of bromine in ethyl acetate analogously to the instructions indicated in Example 29 (a). After distilling off the solvent under reduced pressure, 2-bromo-6-chloro-1-tetralone is obtained as an amorphous residue, which is used without further purification.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[CH2:22][CH:23](O)[CH3:24])[CH:17]=[CH:18][CH:19]=1.[CH2:27]([N:29](CC)CC)C>ClCCl>[CH3:27][NH:29][CH:23]([CH2:22]/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:13]([CH3:26])[CH3:12])[CH:15]=1)[CH3:24]
Reactant: CC(O)C/C=C/c1cccc(N(C)C)c1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC(C)C/C=C/c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
p-Toluenesulfonyl chloride (782 mg, 4.10 mmol) was added, in one portion, to a stirred solution of (4E)-5-(3-(dimethylamino)phenyl)-4-penten-2-ol (648 mg, 3.16 mmol) in triethylamine (2 mL) and dichloromethane (5 mL) at 10° C. under nitrogen. The cooling bath was removed, and the mixture was stirred at 25° C. for 18 h. Saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture was vigorously stirred for 2 h. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The combined organic layers were dried (Na2SO4) and evaporated, and the residue was combined with DMF (1 mL) and 40% aqueous methylamine (3 mL). This mixture, also biphasic, was vigorously stirred at 25° C. for 18 h, poured into a mixture of 30% aqueous NaOH (1 mL) and saturated aqueous NaCl (25 mL), and extracted with ether (3×20 mL). The ether extracts were dried (Na2SO4) and evaporated, and the residue was chromatographed on 30 g of Merck silica gel 60 (70-230 mesh) with 5% (v/v) methanol, 5% triethylamine (v/v) in benzene. This gave 206 mg (29.9% yield) of yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:16])[C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)Nc2cc(Br)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)c2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
In a 25-mL, round-bottomed, single-necked flask was placed 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (500 mg, 2.07 mmol) in DMF (5 mL). The mixture was cooled to 0° C. followed by an addition of NaH (60%, 99.55 mg, 2.49 mmol). The reaction mixture was stirred at 0° C. for 20 min. To this was added MeI (0.39 ml, 6.22 mmol) at 0° C. Then, it was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with sat. NH4Cl (5 mL) and the organic layers were extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% Hexane to 100% EtOAc) to give 455 mg (86%) of 6-bromo-1,3,3-trimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH2:22])=[C:16]([Cl:30])[CH:15]=1.P(Cl)(Cl)Cl>>[Cl:30][C:16]1[CH:15]=[C:14]([NH:13][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([I:1])[C:3]=2[OH:12])[CH:19]=[C:18]([CH3:20])[C:17]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[CH2:22]
Reactant: C=C(c1ccc(Cl)cc1)c1c(C)cc(N)cc1Cl
Reactant: O=C(O)c1cc(I)cc(I)c1O
Solvent: ClP(Cl)Cl
Product: C=C(c1ccc(Cl)cc1)c1c(C)cc(NC(=O)c2cc(I)cc(I)c2O)cc1Cl

Procedure:
Using the reaction sequence of Example 4, 3,5-diiodosalicylic acid is reacted with 1-(4-amino-2-chloro-6-methylphenyl)-1-(4-chlorophenyl)ethylene in the presence of phosphorus trichloride to give N-[3-chloro-5-methyl-4-[1-(4-chlorophenyl)ethenyl]phenyl]-3,5-diiodo-2-hydroxybenzamide. The benzophenone used as starting material for the Wittig reaction was prepared by reacting 4-chlorobenzyl cyanide with 3-chloro-5-methyl-1-nitrobenzene followed by oxidation with alkaline peroxide as known in the literature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:19])([F:18])[F:20])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=3)=[O:41])[CH:3]=[C:4]([F:30])[C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Product: COc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3+MeOD) δ ppm 2.83 (dd, J=13.9, 3.8 Hz, 1H), 3.14 (dd, J=13.9, 3.0 Hz, 1H), 3.29-3.39 (m, 1H), 3.87 (d, J=8.3 Hz, 1H), 4.04 (s, 3H), 4.60 (d, J=8.3 Hz, 1H), 4.67 (quin, J=6.3 Hz, 1H), 7.11-7.21 (m, 1H), 8.03 (ddd, J=11.6, 6.9, 2.7 Hz, 1H), 8.15 (d, J=1.3 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12](Br)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[SH:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[OH-].[Na+].O>CCO>[C:13]1([C:12]2[S:21][C:22]3=[N:26][CH:25]=[CH:24][N:23]3[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ncc[nH]1
Reactant: CS(=O)(=O)c1ccc(C(=O)C(Br)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)sc3nccn23)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8 %

Procedure:
A mixture of the bromoketone of step 2 of example 8 (141.2 mg, 4 mmol), 2-mercaptoimidazole (400 mg, 4 mmol) and NaOH (400 μL, 10 N) in EtOH (4 mL) was stirred at r.t. for 6 h. H2O was added and the precipitate that formed was filtered. The solid was washed with water and dried under vaccum. The dried solid residue (234 mg) was heated with P2O5 (900 mg) in PPA (3.5 mL) at 170 ° C. for 20 h. The mixture was quenched with ice and NH4OAc and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to a solid. The solid residue was chromatographed on silica gel (eluted with 40 % EtOAc/Hexane) to give 113 mg of the title compound. 1H NMR (CD3COCD3): δ3.10 (s, 3H), 7.40-7.20 (m, 7H), 7.65 (d, 2H), 8.00 (d, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34].CO.C(Cl)Cl.N>[Pd].CO.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: I
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 52.7 %

Procedure:
A round bottom flask containing tert-butyl 2-hydroxyethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (220 mg, 0.574 mmol) under argon was charged with palladium on activated carbon (10% wt; 61.0 mg, 0.057 mmol). The mixture was purged with argon prior to the addition of EtOH (20 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 3 hours. The hydrogen balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (327 mg, 1.147 mmol) was added to the reaction. The suspension was stirred at room temperature for 17 hours (overnight). After this time, the mixture was filtered through a pad of Celite, which was then rinsed with MeOH (10 mL). The filtrate was concentrated, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH/CH2Cl2 followed by 3.5:96.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (140 mg, 52.7%). 1H-NMR (DMSO-d6) δ 7.69 (brd, J=3.0 Hz, 1H), 7.57 (d, J=5.1 Hz, 1H), 7.07 (dd, J=3.9, 4.8 Hz, 1H), 6.82-6.75 (m, 1H), 6.53-6.42 (m, 2H), 6.32 (brs, 2H), 4.73 (t, J=5.4 Hz, 1H), 3.54 (brs, 2H), 3.50-3.42 (m, 2H), 3.38 (brs, 4H, overlap with solvent peak), 3.27-3.19 (m, 2H), 3.08-2.96 (m, 2H), 1.41 (brs, 9H); ESI-MS (m/z, %): 463 (MH+, 100), 398 (60); HPLC purity: 96.4% a/a.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with methanesulfonyl chloride (50 μL, 0.57 mmol ). The reaction was stirred at 25° C. for 7 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylamino-phenyl)-N-thiazol-2-yl-propionamide (98.2 mg, 49.9%) as a tan solid: mp 85-90° C.; EI-HRMS m/e calcd for C18H23N3O3S (M+) 393.1180, found 393.1185.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].O=C(Cl)[O:12][C:13](Cl)(Cl)[Cl:14].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:14][C:13]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
3,4-Dichlorophenol (2.35 g) was dissolved in anhydrous dichloromethane (50 ml) at room temperature under an atmosphere of argon. The mixture was cooled to −30° C. and diphosgene (3.92 g) and N,N-Diisopropylethylamine (2.51 ml) were added slowly in the order specified. The resulting solution was then stirred at 0° C. for 3 hours, then at room temperature for 18 hours and finally at reflux for 2 hours. The solution volume was measured and used accordingly.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](Br)=[CH:12][N:13]=[C:7]2[C:6]=1[F:15])=[O:4].[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[C:27](B3OCC(C)(C)CO3)[CH:26]=[CH:25][C:24]=2[F:37])=[CH:21][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:27]3[CH:26]=[CH:25][C:24]([F:37])=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=4[C:38]#[N:39])[CH:28]=3)=[CH:12][N:13]=[C:7]2[C:6]=1[F:15])=[O:4]
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: COC(=O)c1ccn2c(Br)cnc2c1F
Product: COC(=O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 52.4 %

Procedure:
3-Bromo-8-fluoroimidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (0.10 g, 0.37 mmol) and 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.15 g, 0.44 mmol) were coupled following the procedure in Example 1 to afford 3-(2′-cyano-2,4′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (79 mg, 53%) as a white solid: δH (400 MHz, CDCl3) 4.00 (3H, s), 7.35 (1H, dd, J 7 and 7), 7.34-7.46 (2H, m), 7.53-7.66 (4H, m), 7.85 (1H, s), 8.24 (1H, d, J 7); m/z (ES+) 408 (100%, [MH]+).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][C:23]([CH3:41])([CH3:40])[N:24]=[C:25]2[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2.Cl.O.[NH4+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:6]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][C:23]([CH3:41])([CH3:40])[N:24]=[C:25]2[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:8])[CH3:7]
Reactant: CC1(C)Cc2c(Br)cccc2C(c2cnc3ccccc3c2)=N1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2c1CC(C)(C)N=C2c1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Tributyl (1-ethoxyvinyl) tin (0.85 mL, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (15.8 mg, 0.022 mmol) were added to a toluene solution (0.9 mL) of 3-(5-bromo-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (806 mg, 2.2 mmol), and after stirring for 3 hours at 100° C., dilute hydrochloric acid was added to temporarily acidify followed by basifying with ammonium water, filtering, concentrating the filtrate and applying the resulting residue to chromatography to obtain 647 mg of the target compound (yield: 89%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]([CH2:18][OH:19])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
Methanesulphonyl chloride (3.55 g) was added dropwise to an ice-cooled solution of 4(S)-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (6.0 g) (see Preparation 91) and triethylamine (3.48 g) in dichloromethane (100 ml) and the mixture stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue partitioned between diethyl ether and water. The two phases were separated and the aqueous layer further extracted with diethyl ether. The organic phases were then combined and washed sequentially with water, dilute aqueous citric acid solution, brine, saturated aqueous sodium hydrogen carbonate solution and brine before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 4(S)-(3,4-dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (8.25 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [97](118 mg) in ethanol (5 mL) was added an aqueous solution of 1N-potassium hydroxide (0.34 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (128 mg) as a white solid.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[O:20][C:19](=[O:21])[C:18]([CH2:28][CH3:29])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>[Pd].C(O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:28][CH3:29])[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCC1(c2ccccc2)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)c1ccccc1
Reaction time: 4 h

Procedure:
Hydrogen gas was allowed to react with a stirred suspension of 2-[4-(4-chlorophenyl)phenyl]-5-ethyl-5-phenyl-1,3-dioxolan-4-one (3.8 g.) and 5% w/w palladium on carbon (0.2 g.) in ethanol (160 ml.) at 55° to 60° C. and atmospheric pressure for four hours. The mixture was diluted with toluene (50 ml.). The solid material was separated by filtration and the filtrate was evaporated. The resultant solid may be purified by high pressure liquid chromatography on "Spherisorb"* 5μ ODS solid phase using an eluant containing acetonitrile (62% v/v), water (37.9% v/v) and phosphoric acid (0.1% v/v) using ultraviolet absorbance at 262 μm for detection to give 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylbutyric acid identical to that obtained in previous examples.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=O)=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][N:2]([CH3:1])[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10]2)[N:16]=1)=[O:18])=[O:24]
Reactant: CNCC(O)CO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CC(O)CO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 19 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methylamino-propan-1,2-diol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (19%) as sticky yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3](OC)=[O:4].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[OH:1][C@@H:2]([CH3:7])[C:3]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4]
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)O
Product: C[C@H](O)C(=O)N1CCCC1
Yield: 99.7 %

Procedure:
(S)-Methyl 2-hydroxypropanoate (30.0 g, 288 mmol) and pyrrolidine (22.5 g, 317 mmol) were stirred at RT for 3 d. The crude product was purified by passing through a SiO2 plug eluting with 80% EtOAc/hexane to afford 41.1 g (99.6%) (S)-2-hydroxy-1-(pyrrolidin-1-yl)propan-1-one (108).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH3:13][Si:14](OS(C(F)(F)F)(=O)=O)([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][C:2]([CH:3]=[CH2:4])=[CH2:1]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)O[Si](C)(C)C

Procedure:
70 μl (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1=R2=R6=H] and 2 ml of anhydrous CH2Cl2 are charged, at 0° C. under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel. 170 μl (1.22 mmoles) of triethylamine (distilled on KOH) and 209 μl (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2-(trimethylsilyloxy)-1,3-butadiene [compound 6 wherein R1=R2=R6=H] is formed “in situ”. The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles) of the product from Example 2 in 2 ml of anhydrous CH2Cl2 is added therein, drop by drop, together with 69 μl (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NaHCO3 are added and the mixture is stirred vigorously for 36 h. 4 ml of water are added to the mixture and the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHCO3, water, a saturated solution of NaCl and is dried on Na2SO4. After filtration the solvent is removed and 59 mg of crude product are obtained. The product is purified by flash chromatography on silica gel column (FCC) eluting with methylene chloride and triethylamine 1%. 18 mg of the wanted product are obtained (crystals). M.p.: 53-54° C. Yield 25%.