Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2ccc(F)c3nc(C)ncc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 53 mg (0.3 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are reacted to give 4-(4-chloro-3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 140 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yield 3 mg of product and 16 mg of the dihydroxy compound Ex. 18.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][CH:6]=1.[C:9]([CH:11]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:10]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH:7]=[CH:11][C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)s1
Solvent: ClC(Cl)Cl
Product: N#CC=Cc1ccc(Cl)s1
Yield: 85.5 %

Procedure:
A solution of 2-chloro-5-formylthiophene (5.68 g., 40 mM) and cyanomethylenetriphenylphosphorane (12.04 g., 40 mM) in chloroform (100 ml.) was heated under reflux for 20 min., and was evaporated to an oily solid. This was triturated with ether (20 ml.) and colourless needles of triphenylphosphine oxide (m.p. 156°-157°) were filtered off, and were washed with ether (10 ml.). The combined filtrates were evaporated, and the residue was distilled under reduced pressure to give 3-(5-chlorothien-2-yl)acrylonitrile (5.62 g., 83%) as a colourless oil, b.p. 100°-104°/0.6mm., which crystallised in needles, m.p. 41°-43° [Found: C, 49.1; H, 2.5; C1, 21.1; N, 8.3; S, 19.1; C7H4ClNS (169.6) requires C, 49.6; H, 2.4; Cl, 20.9; N, 8.3; S, 18.9%]λmax. 315 nm (ε 21,120).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].[C:19]([O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([CH3:22])([CH3:21])[CH3:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:19]([O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH:16]([CH3:18])[CH3:17])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:43][CH:44]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([CH3:21])([CH3:22])[CH3:20]
Reactant: Cc1c(C(=O)O)oc2ccc(Cl)c(OC(C)C)c12
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
To 80 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid was added 121 mg of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, 159 mg of BOP, 46 mg of N,N-diisopropylethylamine and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. The mixture was addedbrine and was extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent and purification of the residue by column chromatography on silica gel gave 178 mg (98% yield) of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as a colorless semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][N:30]=[C:31]=[O:32])[CH3:26].CO>ClCCl>[CH2:25]([O:27][C:28](=[O:33])[CH2:29][NH:30][C:31]([O:24][C@@H:13]([C:9]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=[CH:11][CH:10]=1)[C@@H:14]1[N:19]2[CH2:18][CH2:17][C@H:16]([C@@H:21]([CH:22]=[CH2:23])[CH2:20]2)[CH2:15]1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CN=C=O
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)OCC)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
To a solution of 200 mg (0.61 mmol) of quinidine in 5 ml of dry dichloromethane was added 74 ml (0.65 mmol) of ethylisocyanatoacetate. The mixture was allowed to stir magnetically at room temperature for 18 h and concentrated under reduced pressure. The residue was purified on preparative thin layer chromatography (silica, 2 mm) using a mixture of 1:9 ethyl acetate:methanol as the eluent and yielded 130 mg (0.28 mmol, 46%) of (8). MS, IR and NMR data confirmed identity of the compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(CBr)cc1F
Temperature: 25 °C
Yield: 220.5 %

Procedure:
1,4-Difluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6 mL) and N-bromosuccinimide (1.54 g) added followed by benzoyl peroxide (0.2 g). The reaction mixture was stirred at reflux for 2.5 hours then additional benzoyl peroxide (0.2 g) and N-bromosuccinimide (1.54 g) were added. The reaction was refluxed for 2 hours then was cooled to room temperature, quenched with water and extracted with dichloromethane (3×). The combined organics were dried and concentrated under reduced pressure. The oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure to yield the title compound (3.21 g).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33].O>CN(C)C=O>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:18]=2)=[CH:11][C:5]2[N:6]([CH2:33][C:32]#[CH:31])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Then, 1.22 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-49) was dissolved in 15 ml of N,N-dimethylformamide, to which 0.59 g of potassium carbonate and 0.47 g of propargyl bromide were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.60 g (total yield in two steps (4) and (5), 25%) of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-61; m.p., 141.4° C.).
Reaction SMILES: C(CC(O)=O)#N.[C:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].C=O.C(=O)=O.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1CC(=C)C#N>CCOCC.C(Cl)Cl.C(O)C.O1CCOCC1>[C:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1
Reactant: C=C(C#N)CN1CCCCC1C
Agent: C=O
Agent: CC(C)(C)C1CCNCC1
Agent: N#CCC(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1CCCCN1
Reaction time: 12 h

Procedure:
Cyanoacetic acid (1.75 g., 0.02 mole) was dissolved in 10 ml. of dioxane. In a five minute period 4-t-butylpiperidine (2.8 g., 0.02 mole) was added, the temperature rose to 25° C. from 15° C. obtained by prior cooling with an ice bath. The mixture which solidified became fluid upon the addition of 37% aqueous formaldehyde (3.6 g., 0.04 mole), the temperature rose to 30° C. and carbon dioxide evolution began. The mixture was stirred an additional 12 hours, was taken up in ether and the organic phase separated and washed with water. The dried ether solution was stripped to solvent to leave a solid residue product, 3.7 g. of practically analytical purity. In place of 4-t-butylpiperidine, the use of 2-methylpiperidine (0.02 mole) provided 2-[(2-methyl-1-piperidyl)methyl]propenenitrile as a colorless oil, RfSiO2 0.58 (5% ethanol in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24](=[O:25])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCC(=O)N1CCCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCC(=O)N1CCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (500 mg, 1.4 mmol) and 3-amino-1-(pyrrolidin-1-yl)propan-1-one (240 mg, 1.7 mmol). The title compound was obtained as a solid (22.0 mg, 3% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.92 (1H, m), 8.43 (1H, s), 3.40 (2H, m), 3.34 (2H, m), 3.26 (2H, m), 2.47 (2H, m), 1.84 (2H, m), 1.73 (2H, m). MS m/z: 475.10, 477.11 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21][CH3:22])=[CH:16][N:15]=2)=[N:6]1.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34]#[N:35].C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[C:34]#[N:35])[C:17]([O:21][CH3:22])=[CH:16][N:15]=2)=[N:6]1
Reactant: N#Cc1cnccc1Br
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C#N

Procedure:
175 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-11-1, 0.501 mmol, 1. eq.), 101 mg of 4-bromopyridine-3-carbonitrile (0.551 mmol, 1.1 eq.), 115 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.125 mmol, 0.25 eq.), 156 mg of 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.25 mmol, 0.5 eq), 144 mg of sodium 2-methylpropan-2-olate (97%) (1.503 mmol, 3 eq.) and 52 ml of N,N-dimethylformamide were stirred under nitrogen atmosphere for 30 minutes at 100° C. and 300 W in a CEM microwave. The reaction mixture was washed with half-saturated aqueous sodium chloride solution. The organic layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/dichloromethane/methanol) and preparative HPLC. A crystallisation from dichloromethane/methanol gave 5.8 mg (0.01 mmol, 2.6%) of the analytically pure target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([Cl:17])[C:12](=O)[N:11]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.CCO.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@@:13]1([Cl:17])[CH2:12][N:11]([C@@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CCC[C@]2(Cl)C1=O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@]2(Cl)CCC[C@@]2(NC(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 14 h
Yield: 32.2 %

Procedure:
Under nitrogen atmosphere, to a solution of (1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (217 mg, 0.573 mmol) in THF (10 mL) was added 1.0M borane-THF complex in THF solution (1.72 mL, 1.72 mmol) at room temperature. After stirring for 14 hours, 1.0M borane-THF complex in THF solution (0.86 mL, 0.86 mmol) was added. The mixture was warmed to 50° C., and stirred for 18 hours. To the mixture was further added 1.0M borane-THF complex in THF solution (0.86 mL, 0.86 mmol) and the mixture was stirred for 24 hours at 50° C. After being cooled to 0° C., to the mixture were added water (1 mL), EtOH (9 mL) and triethylamine (1 mL). The mixture was warmed to 80° C., and stirred for 2 hours. The solvent was distilled off under reduced pressure. To the residue were added saturated aqueous solution of ammonium chloride and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flush column chromatography (10% ethyl acetate/hexane) to afford 67.3 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[C:28](=O)[CH:27]=[C:26]([O:32]C)[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]I>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:25][C:26](=[O:32])[CH:27]=[C:28]([CH3:34])[CH:29]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(OC)=CC(=O)C2C)c(OCc2ccccc2)c1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(C)C2C)c(OCc2ccccc2)c1

Procedure:
Following the procedure of Example 1, 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methoxy-6-methyl-2-cyclohexen-1-one is reacted via the Grignard reaction with methyl magnesium iodide to give the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccs3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.95 g of 4,5-bis(4-methoxyphenyl)-2-(2-thienylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.47 g of 4,5-bis(4-methoxyphenyl)-2-(2-thienylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.Cl>O1CCCC1.O.CO.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COCCOCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COCCOCOc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
15 g (375 mmol) of sodium hydroxide powder are added to a solution of 16 g (75 mmol) of methyl 4-(2-methoxyethoxymethoxy)benzoate in 250 ml of tetrahydrofuran, 80 ml of water and 30 ml of methanol. The reaction medium is stirred at 40° C. for 18 h then hydrolysed, diluted with ethyl acetate and brought to pH=6 with an aqueous solution of hydrochloric acid having a concentration of 1N. After extracting with ethyl acetate, the organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered then concentrated. 16 g (95%) of 4-(2-methoxyethoxymethoxy)benzoic acid are obtained in the form of a white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9](O)=[O:10].S(Cl)([Cl:22])=O>>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9]([Cl:22])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)Cl
Yield: 106.3 %

Procedure:
To a 100-ml three-necked round flask (equipped with stirrer chip, Dimroth condenser, thermometer and NaOH trap) were introduced 13.3 g (52.4 mmol) of the 3-(2-biphenylyl)-2-ethylpropionic acid and 25.9 ml (355 mmol) of thionyl chloride, and they were refluxed for 2.5 hours with heating in a nitrogen atmosphere. After the reaction was completed, the unreacted thionyl chloride was distilled off under reduced pressure to obtain 15.2 g of a crude product of yellow orange liquid. This acid chloride was used for the next reaction without further purification. The properties of the product thus obtained are described below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21]([O:23]C)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:23])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Yield: 63.4 %

Procedure:
(S)-Methyl 1-(4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanamido)-3-bromo-1H-pyrrole-2-carboxylate (1 g, 1.96 mmol) was treated with aniline (893 μl, 9.8 mmol) and trimethyl aluminium (2 M in toluene, 4.9 mL, 9.8 mmol) according to the method of Preparation 10a. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) a to obtain 0.71 g (63% yield) of the title compound. Purity 100%.
Reaction SMILES: CC([O-])(C)C.[Na+].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([C:64](=[O:69])[CH2:65][CH2:66][CH2:67][CH3:68])=[CH:60][CH:59]=1.Br[C:71]1[CH:83]=[CH:82][C:74]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])=[CH:73][CH:72]=1.C([O-])(O)=O.[Na+]>CCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([C:64](=[O:69])[CH:65]([C:71]2[CH:83]=[CH:82][C:74]([C:75]([O:77][C:78]([CH3:79])([CH3:80])[CH3:81])=[O:76])=[CH:73][CH:72]=2)[CH2:66][CH2:67][CH3:68])=[CH:62][CH:63]=1
Reactant: CCCCC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCCC(C(=O)c1ccc(Cl)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl(aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1: 1.35 min. (M-tBu+H)+ 317.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=3)[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:34][CH:33]=4)=[O:37])[CH:15]=3)[C:11]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(N)c3)nn12
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
6-(3-Amino-phenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester (33 mg, 0.091 mmol) was dissolved in dry DCM (0.5 mL) under nitrogen atmosphere. p-Trifluoromethylphenylisocyanate (0.014 mL, 0.100 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to dryness and the crude product was purified by chromatography on silica gel (DCM/MeOH 97:3) to give 31 mg (61%) of 7-pyridin-4-yl-6-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester.