Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:30][C:31]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:32])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride salt (0.17 mmol, 70 mg), ethylchloroformate (0.25 mmol, 25 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided compound A123 as a white solid (14 mg, 15%). Exact mass calculated for C20H23N5O5S 445.49, found 446.10 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9].CC[O:15][C:16]([CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([N:11]2[C:16](=[O:15])[CH:18]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:12]2)=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9]
Reactant: C#CCc1sc(F)c(NN)c1Cl
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: C#CCc1sc(F)c(N2N=C3CCCCC3C2=O)c1Cl
Yield: 56.1 %

Procedure:
A mixture of 4-chloro-2-fluoro-5-propargylthiophenylhydrazine (1.2 g), ethyl 2-cyclohexanonecarboxylate (0.85 g) and acetic acid (10 ml) was heated under reflux for 2 hours, followed by cooling. Water was added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue was crystallized from a mixture of n-hexane and ether to give 0.87 g of 2-(4-chloro-2-fluoro-5-propargylthiophenyl)-3,3a,4,5,6,7-hexahydro-2H-indazol-3-one. M.P., 170°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][O:26][CH3:27]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][O:26][CH3:27])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCl
Reactant: N#Cc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
To a suspension of 4-cyano-N-thiazol-2-yl-benzenesulfonamide (10 mmol) and potassium carbonate (15 mmol) in DMF (30 mL) was added chloro-methoxy-methane (10 mmol) and the mixture was stirred for 4 h. The reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (8.2 mmol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=[N+]([O-])O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of 6-bromopyridin-3-ol (2.5 g, 14.4 mmol) in acetic acid (20 mL) at 0° C. was added fuming nitric acid (0.9 mL, 22.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 1 hour. The reaction mixture was cooled to 0° C. and 10M aqueous hydroxide was added dropwise until pH 4-5 (ca 25 mL). The resulting mixture was diluted with water and partially concentrated under reduced pressure. The residue was extracted twice with EtOAc. The organic fractions were combined and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was azeotroped with toluene to give 6-Bromo-2-nitropyridin-3-ol as an orange solid (2.2 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1 H); 7.86-7.83 (d, J=8.6 Hz, 1 H); 7.61 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1C2C(=CC=C(O)C=2)N[N:30]=1.N12CCCN=C1CCCCC2>ClCCl>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][P:11]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:1][N:30]=1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 497 mg of 50%-pure methylphenylphosphinic acid 4-nitrophenyl ester in 8 ml of dichloromethane is stirred at ambient temperature. A suspension of 403 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 268 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 12 ml of dichloromethane is added dropwise. The reaction medium is stirred at ambient temperature overnight and then evaporated to dryness under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography on a cartridge of 50 g of silica 15-35 μm. 300 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester are collected and recrystallized from ethyl acetate to obtain 220 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([Sn]([C:25]#[N:26])(CCCC)CCCC)CCC.O.[Cl-].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Cl-].[Cl-]>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.ClC(Cl)C>[C:25]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)#[N:26]
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2c(c1)NC(=O)C2
Reaction time: 6 h
Yield: 30.2 %

Procedure:
6-Bromo-1,3-dihydro-indol-2-one (0.621 g, 2.93 mmol), tributyltin cyanide 1.11 g, 3.5 mmol), tetraammonium chloride hydrate (0.97 g, 5.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.21 g, 0.3 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.342 g, 0.3 mmol) were treated with dichloroethane (100 mL) and the reaction refluxed for 16 h under nitrogen with stirring. A further addition of tetrakis (triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) was made and reflux continued a further 6 h. A third addition of tetrakis (triphenylphosphine)palladium(0) (0.345 9, 0.3 mmol) was made and the reaction returned to reflux for 16 h. On cooling the reaction solution was washed twice with an aqueous solution of potassium fluoride (50 mL) and the organic phase dried over magnesium sulfate, filtered and evaporated to dryness. The product was subjected to chromatography on silica gel using dichloromethane to give 140 mg of 6-cyano-1,3-dihydro-indol-2-one contaminated with triphenylphosphine oxide. A second chromatographic purification chromatography on silica gel using dichloromethane gave 61 mg of pure 6-cyano-1,3-dihydro-indol-2-one; 1H-NMR (DMSO-d6): δ10.64 (bs, 1H), 7.37 (s, 2H), 7.10 (s, 1H), 3.56 (s, 2H). Mass spectrum (negative ion electrospray): m/z=157 (M−1, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:24])[F:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH:22]([F:23])[F:24])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18.25 h

Procedure:
4-[5-(1-Cyclohexenyl)-3-(difluromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10% palladium on charcoal was added, and the suspension was stirred at room temperature under hydrogen (36 psi) for 18.25 hours. The reaction was filtered through celite, and the ethanol removed in vacuo to give a white solid, which was recrystallized from methylene chloride/isooctane (0.31 g, 99%): mp 199-203° C.; 1H NMR (acetone-d6) 300 MHz 8.05 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0 Hz 1 H), 6.47 (s, 1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71-1.88 (m, 5H), 1.24-1.43 (m, 5H); 19F NMR ( acetone-d6) 300 MHz: −112.86 (d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C@@H:5]([CH3:39])[CH2:6][CH:7]([NH:22][C:23]([C:25]1[N:26]=[N:27][N:28](CC2C=CC(OC)=CC=2)[N:29]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:40])[C@H:5]([CH3:39])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[N:29]=[N:28][NH:27][N:26]=1)=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn[nH]n1

Procedure:
Next, a solution of (S)-5-(3′-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester (212 mg, 0.377 mmol) in TFA (5 mL) is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is purified by chiral HPLC on a Chirapak IA column using heptane/ethanol (80:20) (0.1% TFA) to elute the title compound; HPLC Retention time 1.59 minutes (condition C): MS 442.2 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.10 (m, 3 H) 1.10-1.16 (m, 3 H) 1.69-1.79 (m, 1 H) 1.88 (ddd, J=13.89, 9.98, 3.92 Hz, 1 H) 2.77-2.87 (m, 1 H) 2.87-2.96 (m, 1 H) 3.91-4.05 (m, J=10.72, 7.14, 7.14, 3.66, 3.66 Hz, 2 H) 4.24 (br. s., 1 H) 6.85-6.85 (m, 0 H) 7.30 (d, J=8.34 Hz, 2 H) 7.37-7.42 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.56-7.64 (m, 3 H) 7.68 (t, J=1.77 Hz, 1 H) 9.18 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4]([NH:71][CH:68]1[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]1)=[O:5]
Reactant: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reaction time: 0.08 h

Procedure:
2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoic acid (65 mg), TBTU (60 mg) and DIPEA (0.1 mL) are suspended in DMF (0.50 mL) and stirred for 5 min. 1-methylpiperidin-4-amine (18 mg) is added and the reaction mixture is stirred for a further 20 min. The reaction mixture is purified by HPLC without working up. (IC50=1 nmol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]2[CH:20]=[N:21][O:22][C:18]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.46 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.48 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 111–112° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH:11]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)(=[O:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc(Br)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
Dissolved the product from Example 39B (3.68 g, 10.05 mmol) in dichloromethane (167 mL) and cooled the solution in an ice bath followed by the addition of triethylamine (4.20 mL, 30.1 mmol) and methanesulfonyl chloride (1.96 mL, 25.1 mmol) dropwise. After stirring for 15 min, the solution was concentrated to a solid (5.25 g, 100%) that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][CH2:16][OH:17])=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:18](O)=O>Cl>[OH:17][CH2:16][CH2:15][N:14]1[C:3]2[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:9])=[O:10])=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:18]1
Reactant: O=CO
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1NCCO
Agent: Cl
Product: CN(C)S(=O)(=O)c1cccc2ncn(CCO)c12

Procedure:
A solution of 3-amino-2-[(2-hydroxyethyl)amino]-N,N-dimethylbenzenesulfonamide (69 mg, 0.266 mmol) in formic acid (2 mL) and 2 M hydrochloric acid (2 mL) was heated at reflux for 1 h. The volatiles were removed in vacuo, and the residue was partitioned between an aqueous sodium hydroxide solution and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo affording 1-(2-hydroxyethyl)-N,N-dimethyl-1H-benzimidazole-7-sulfonamide, 66 mg. MS (ES) m/z 270 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])C.[OH-].[Na+]>CO.O>[C:21]([O:20][C:18]([NH:17][C@H:6]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F

Procedure:
(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45° C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (9.2 g) as a white solid, which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:23]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:21][C:22](=[O:23])[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(OCC(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-methoxybenzoic acid methyl ester (2.50 g, 13.7 mmol) was dissolved in methanol (20 ml), potassium carbonate (3.72 g, 27.4 mmol) and 2-bromo-1-m-tolyl-ethanone (2.92 g, 13.7 mmol) were added and the mixture was stirred overnight at room temperature. The volatiles were evaporated, the crude material was partitioned between EA and water, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2c(Cl)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2c(Cl)cccc2C1=O
Yield: 81 %

Procedure:
A solution of 14.0 g of 4-chloro-1-indanone, 17.3 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 15.2 g (81%) of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:22].[C:23]1([C:29]2[NH:30][C:31]([CH3:37])=[C:32]([CH:34]([Cl:36])[CH3:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:30][C:31]=3[CH3:37])[CH3:35])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1C(C)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol:water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4-[1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl]piperazine trihydrochloride, which melted at 215° C.
Reaction SMILES: O.Br[CH2:3][C:4]1[C:5]([Cl:22])=[CH:6][C:7]([Cl:21])=[C:8]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:9]=1.C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:15][C:14]1[C:10]([C:8]2[C:7]([Cl:21])=[CH:6][C:5]([Cl:22])=[C:4]([CH:9]=2)[CH:3]=[O:34])=[N:11][N:12]([CH3:20])[C:13]=1[O:16][CH:17]([F:19])[F:18]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Yield: 56.3 %

Procedure:
After addition of 100 ml water to a solution of 3-(5-bromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (26.60 g, 63.3 mmoles) in 100 ml glacial acetic acid, hexamethylenetetramine (8.87 g, 63.3 mmoles) was added and reacted under reflux for 2 hours. Further, 40 ml conc. sulfuric acid was added and reacted under reflux for 13 hours. Then the reaction product mixture, poured into ice-cold water, was extracted with ethyl acetate. The extract solution was washed with 5% aqueous NaHCO3 and then with water, dehydrated, and concentrated. Purification of the residue by column chromatography gave the title compound (12.66 g), m.p. 138.2° C., yield 56.3%.