Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cc2ccccc2[nH]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (17.10 g, 68.6 mmole) was added to a solution of 2-(methylaminomethyl)-1H-indole (10.00 g, 62.4 mmole), from Preparation 33, and triethylamine (9.60 mL, 68.6 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title compound (14.80 g, 80%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[CH:17](O)=[O:18]>>[CH:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)=[O:18]
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: O=CO
Product: O=COCc1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 75 %

Procedure:
2-(Hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (3.3 g, 0.0153 mole) is suspended in 250 ml of 97-100% formic acid and refluxed overnight under nitrogen. The solution is stripped to dryness and the solid is recrystallized from dioxane to give 2.8 g (75% yield) of analytically pure title compound, m.p. 190°-192°.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:19])=O)C1C=CC=CC=1.[N:26]1[C:35]2[C:30](=[N:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.N1CCCCC1>CC(O)C>[N:31]1[C:30]2[C:35](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:34]=[CH:33][C:32]=1[CH:36]=[C:15]1[NH:11][C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:19])=[N:13][C:14]1=[O:16]
Reactant: Cc1ccsc1C(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: Cc1ccsc1C(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-[(3-methyl-thiophene-2-carbonyl)-amino]-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (42.0 mg, 0.12 mmol), 1,5-naphthyridine-6-carboxaldehyde (18.6 mg, 0.12 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 3-methyl-thiophene-2-carboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light yellow solid (13.3 mg, 30.5%). HR-ES (+) m/e calcd. for C18H13N5O2S: (M+H)+ 364.0863. Found: 364.0862.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(F)cc3F)cc2)c1C
Yield: 32.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.184 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.082 g, 33%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].C(O)(=[O:36])C.[Se](=O)=O>O1CCOCC1>[OH:36][CH2:22][C:5]1[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3](=[O:33])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[C:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[N:12]=[CH:11][CH:10]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(CO)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 1) (50.0 mg) in dioxane (1.0 ml) were added acetic acid (0.5 ml) and selenium dioxide (74.0 mg) and the resulting mixture was stirred with heating under reflux for six hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6-hydroxymethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.7 mg).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[C:34]([C@H:37]1[CH2:41][CH2:40][NH2+:39][CH2:38]1)([OH:36])=[O:35].CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:39]3[CH2:40][CH2:41][C@H:37]([C:34]([OH:36])=[O:35])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)[C@H]1CC[NH2+]C1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.2 g, 2.9 mmol) was added to a solution of (3S)-3-carboxypyrrolidinium trifluoroacetate (0.50 g, 2.3 mmol) and DIPEA (3 mL, 17 mmol) in DCE (20 mL) at 80° C. The reaction mixture was stirred for 2 hrs. and the solvent was concentrated. The product was purified by MPLC on silica gel using 30% acetone in DCM containing 1% of AcOH to provide the title compound as white solid. Yield: 600 mg (42%); MS (ESI) (M+H)+=484.1.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:38]Br>C(Cl)(Cl)Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH:31]([Br:38])[CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: BrBr
Reactant: CCCC(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (300 mg, 0.554 mmol) in CHCl3 (3 mL) at 0° C. under N2, was added dropwise a solution of bromine (0.030 mL, 0.582 mmol) in CHCl3 (2 mL). The reaction was stirred at 0° C. for 1 h. The reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutanoyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS calc.=622.0; found=621.7 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.91 (s, 1 H); 7.85 (d, J=5.1 Hz, 1 H); 7.83-7.77 (m, 2.5 H); 7.74-7.69 (m, 1.5 H); 5.79 (d, J=7.8 Hz, 0.5 H); 5.74 (d, J=7.9 Hz, 0.5 H); 5.06-4.92 (m, 2 H); 4.57 (d, J=16.4 Hz, 0.5 H); 4.47 (d, J=16.0 Hz, 0.5H); 4.24-4.16 (m, 1 H); 2.35-2.25 (m, 1 H); 2.19-2.09 (m, 1 H); 1.18-1.16 (m, 3 H); 0.80 (d, J=6.6 Hz, 1.5 H); 0.78 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:16]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
47 mg of the target compound (0.13 mmol, 23.8%) was obtained using 1-(2-methoxyphenyl)piperazine (209 mg, 1.09 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1>C(O)(C)(C)C>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:9])([CH3:20])([CH3:15])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCNCC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1CCNCC1
Temperature: 25 °C

Procedure:
12.9 g of 4-piperidine carboxylic acid is completely dissolved in 35 ml of t-butyl alcohol (R1OH) and refluxed for 10 hrs. in the presence of 3.8 g of para-toluene sulfonic acid. After being cooled to room temperature, the resulting reaction is washed three times with 20 ml of saturated NaHCO3 and then, once with 25 ml of brine water and dried over MgSO4 to give piperidine-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][CH:19]1[CH:20]2[CH2:28][CH:24]3[CH2:23][C:22]([OH:29])([CH2:27][CH:26]1[CH2:25]3)[CH2:21]2)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 3-(benzyloxy)benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.69-7.74 (m, 1H), 7.29-7.48 (m, 7H), 7.20-7.24 (m, 0.5H), 7.09-7.13 (m, 0.5H), 6.27 (d, 1H), 5.12 (s, 2H), 4.18-4.23 (m, 1H), 2.16-2.27 (m, 3H), 1.91-1.98 (m, 2H), 1.71-1.84 (m, 6H), 1.54-1.61 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[O:7][CH2:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[C:14]([N:12]1[CH:13]=[C:9]([CH2:8][O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:35]=[CH:34][CH:33]=2)[N:10]=[CH:11]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Yield: 42.8 %

Procedure:
A mixture of 4-(3-nitro-phenoxymethyl)-1-trityl-1H-imidazole (1.5 g, from above) and 10% Pd/C (0.18 g) in ethyl acetate (60 mL) and ethanol(30 mL) was hydrogenated at 1 atmosphere overnight. The reaction mixture was filtered through a celite pad and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (40:60) to afford 3-(1-trityl-1H-imidazol-4-ylmethoxy)phenylamine (0.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)=[O:54])[CH3:51]>C(OCC)(=O)C>[CH2:50]([O:52][C:53]([N:55]1[CH2:56][CH2:57][N:58]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH:17]([F:19])[F:18])[CH2:59][CH2:60]1)=[O:54])[CH3:51]
Reactant: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 114 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid were added 0.11 ml N-ethylmorpholine, 138 mg TOTU and 66 mg 1-ethoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 168 mg
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1=CCCCC1
Temperature: 120 °C

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (1 g, the compound of Reference Example 1 from EP 295,117) and cyclohexanone (1.6 ml) in acetic acid (5 ml) was stirred and heated at 120° C. overnight under an atmosphere of nitrogen. The cooled reaction mixture was diluted with water and extracted with ethyl acetate and then ether. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then water. After drying (MgSO4), evaporation gave the crude product which was purified by column chromatography on silica gel (50 g) eluted with dichloromethane:hexane (1:2), then dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions provided the title compound as a white solid m.p. 175-7° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[CH3:7][C:8]([CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][CH2:11]1)=[O:9]>>[CH3:16][C:14]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH:10]([C:8]([OH:9])([CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH3:7])[CH2:15]1
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CC(C)CCBr
Product: CC(C)CCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 3-methyl-1-bromobutane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH:19]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
Sodium hydride (63%, 25 g, 656 mmol) was added to a solution of 4-methoxybenzyl alcohol (90.3 g, 654 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (US200216506 A1, 156 g, 544 mmol) in DMF (1.4 L) at room temperature, and the mixture was stirred at 80° C. for four hours. After leaving to cool, water (1.5 L) was added to the reaction mixture. The precipitated solid was collected by filtration to obtain the title compound (209 g, 99%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a stirred solution of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol) in DMF (60 mL) is added tert-butyldimethylsilyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol). The reaction is stirred at room temperature for 18 h, diluted with 1 L of water and extracted with a 1:1 (2×200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine, dried with NaSO4, and concentrated under vacuum. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S, 6R)-3-(tert-butoxycarbonyl) aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one as a white solid, melting point: 65-66° C.; 1H NMR (CDCl3) δ 5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=O)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH3:17][O:16][C:8]1[C:9]2[O:10][C:11](/[CH:14]=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:12][C:13]=2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-methoxybenzo[b]furan-4-carboxylate (from step 7) (2.0 g, 8.53 mmol) in toluene (50.0 mL) was added malonic acid (1.33 g, 12.80 mmol) and Piperidine (0.5 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×100 mL0 and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (1.8 g) as light yellow solid.
Reaction SMILES: [N:1]1([S:6]([C:9]2[NH:10][C:11](=[O:15])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:10]=2)(=[O:8])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=c1cccc(S(=O)(=O)n2cccc2)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(S(=O)(=O)n2cccc2)n1

Procedure:
To a stirred solution of 2-(pyrrole-1-sulphonyl)pyrid-6-one (0.22 g) in dichloromethane (20 cm3) under nitrogen at 0° C. was added in solution of mesyl chloride (0.124 g) in dichloromethane (5 cm3) and triethylamine (0.109 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 3-Amino-5-bromobenzotrifluoride (200 mg) in pyridine (2 mL) was added methane sulphonyl chloride (115 mg) and one crystal of 4-(dimethyl-amino)pyridine. The mixture was stirred at room temperature for four hours then diluted with ethyl acetate (50 mL) and washed with HCl (2M, 50 mL) and saturated sodium chloride solution (50 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield N-(3-bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (264 mg).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:31][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:32][N:33]([CH3:62])[CH2:34][CH2:35][O:36][C:37]1C=CC(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)=[CH:39][CH:38]=1>>[CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:17])[CH3:18])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH3:62])[CH3:32])=[CH:31][CH:30]=5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CN(C)CCOc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(CN(C)C)cc(N4C5CCC4COC5)n3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea was used, using 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.034 g, 18%. MS; 546.5, M+H.