Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28]([OH:30])=O)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[C:62]([NH2:67])=[CH:63][CH:64]=[CH:65][CH:66]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][C:28](=[O:30])[C:27]([N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:31]
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)acetic acid (10.3 g), HOBt (4.13 g) and WSC.HCl (6.28 g) were dissolved in DMF (50 ml), N-(4-methoxybutyl)benzene-1,2-diamine (4.67 g) and diisopropylethylamine (11.3 ml) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11](NC1C=CC(CN2CCOCC2)=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:42]([C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48]2)([O-:44])=[O:43].C(O)(C(F)(F)F)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:28]([CH:39]([CH3:41])[CH3:40])=[CH:27][C:10]=1[C:11]([N:49]1[CH2:48][C:47]2[C:51](=[CH:52][CH:53]=[C:45]([N+:42]([O-:44])=[O:43])[CH:46]=2)[CH2:50]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (505 mg; 1.3 mmol) (Preparation B5), 5-nitroisoindoline, TFA (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3 (270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight then evaporated in vacuo The residue was partitioned between EtOAc and 2M HCl, the EtOAc layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:4 then 1:2 then 1:1 EtOAc/P.E. as eluant) gave 460 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl) methanone. MS: [M+H]+ 328.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:20])=[CH:5]2.[CH:21]1[C:34]2C=C(O)C3C(=CC=CC=3)C=2C=C[CH:22]=1>>[OH:19][CH:13]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[OH:12])=[CH:34][CH:21]=[CH:22][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Oc1cc2ccccc2c2ccccc12
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1O
Product: CCOC(=O)C(O)c1c(O)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate in Example 20, using phenanthren-9-ol instead of 6-bromo-3-methylnaphthalen-1-ol. 1H-NMR: 400 MHz, (CDCl3) δ: 8.90 (s, 1H), 8.66-8.62 (m, 2H), 8.40 (d, J=4.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.71-7.49 (m, 4H), 6.23 (s, 1H), 4.14-4.08 (m, 2H), 3.81 (bs, 1H), 1.11 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:28][CH2:27][CH2:25][CH2:24]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:33]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(C(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)—N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)—N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and 3-(trifluoromethyl)benzoyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.41-8.17 (m, 1H), 8.14-8.05 (m, 1H), 8.01-7.78 (m, 1H), 7.76-7.66 (m, 1H), 7.53 (t, J=7.6, 1H), 4.51-4.29 (m, 1H), 4.20-4.00 (m, 1H), 3.89 (ddd, J=12.0, 6.6, 1.5, 1H), 3.74 (tdd, J=8.3, 5.2, 2.8, 1H), 3.67-3.45 (m, 1H), 3.32-3.13 (m, 2H), 2.87-2.57 (m, 6H), 2.23-2.02 (m, 1H), 1.96-1.78 (m, 2H), 1.73-1.55 (m, 6H), 1.47-1.24 (m, 1H), 1.04-0.79 (m, 6H); MS (ESI+) m/z 466 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Br:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: SCc1ccc(Br)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccc(CSCc2ccc(Br)cc2)cc1
Yield: 91 %

Procedure:
To a solution of 1.85 g (9.11 mmol) of 4-bromobenzylmercaptan in dry dichloromethane (30 ml) were added 2.72 g (10.9 mmol) of 4-bromobenzyl bromide and 2.31 g (22.8 mmol) of triethylamine in an atmosphere of argon, and the mixture was allowed to react at room temperature for 16 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetate-hexane (1:4) yielded 3.08 g (8.29 mmol) of bis(4-bromobenzyl)sulfide.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
A small screw cap test tube was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.2401 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (45.9 mg, 0.240 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 59% yield (0.0835 g, 0.142 mmol).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[S:13]([F:16])(=[O:15])=[O:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)(=O)C>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([C:8]([C:9]([O:10][C:11]([C:12]([S:13]([F:16])(=[O:14])=[O:15])([F:17])[F:18])([F:19])[F:20])([F:22])[F:21])([F:24])[F:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
7.82 g (100 mmol) of benzene, 8.52 g (20 mmol) of 5-iodooctafluoro-3-oxapentanesulfonyl fluoride, 4.84 g (20 mmol) of benzoyl peroxide, 0.36 g (2 mmol) of copper (II) acetate, and 100 mL of acetic acid were refluxed for 4 hrs at 115° C. Then the mixture was stirred at room temperature overnight. The mixture was diluted with water (˜100 mL), and the product was extracted with hexane and washed with water until neutral pH was obtained. The solvent was removed to yield dark yellow oil. The product was purified by distillation under reduced pressure (˜27 inch Hg). The first faction was composed of a mixture of the product plus iodobenzene (2.8 g, approximately 1:1 ratio). The second fraction consisted of 2.1 g of pure product (colorless oil) (28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: CCC(=O)Cl
Solvent: CCOCC
Product: CCC(=O)Nc1cc(OC)cc2c1CC(C)O2

Procedure:
The compound of the title is prepared according to the procedure described in Example 10 by reacting the starting 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with propionyl chloride instead of ethylchlorocarbonate. M.p. 101°-02° C. (from ethyl ether). Yield 44 grams (75 percent of theoretical).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:2]=1.[OH-].[Na+].[CH3:14]I>C(O)C>[CH3:14][N:9]1[N:10]=[N:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8]1
Reactant: CI
Reactant: c1cncc(-c2nnn[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnc(-c2cccnc2)n1
Yield: 29.4 %

Procedure:
5-(3-pyridyl)-tetrazole (11) (J. M. McManus and R. M. Herbst, J. Am. Chem. Soc., 24 (1959) 1462-64) (10 g, 0.068 mol), sodium hydroxide (2.73 g, 0.068 mol), and methyl iodide (14.5 g, 0.1 mol) in ethanol (100 ml) was stirred at 40° C. overnight. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane (100 ml), and the solution was washed three times with water (100 ml). The organic phase was dried over magnesium sulphate and evaporated yielding 3.21 g (0.020 mol, 30%) of 12 with M.P. 108°-110° C. According to the 1H NMR spectrum the product contained less than 10% of the 1-isomer.
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]([CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)[CH3:5]>C(OCC)(=O)C>[I-:2].[CH3:3][N+:4]([CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)([CH3:1])[CH3:5]
Reactant: CI
Reactant: COC(=O)c1cccc(-n2cccc2CN(C)C)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2cccc2C[N+](C)(C)C)c1
Product: [I-]
Reaction time: 2 h

Procedure:
Methyl iodide (4.8 ml) was added dropwise to the mixture of methyl 3-(2-dimethylaminomethylpyrrol-1-yl)benzoate (10.0 g) and ethyl acetate (50 ml) at ambient temperature, and the mixture was stirred for 2 hours at the same temperature. The isolated precipitate was collected by filtration and dried to give methyl 3-(2-trimethylammoniomethylpyrrol-1-yl)benzoate iodide (13.52 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@@H:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:20][OH:21])[C:15]([F:26])=[CH:14][N:13]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@@H:19]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:20]=[O:21])[C:15]([F:26])=[CH:14][N:13]=1
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[C@@H](C=O)Nc1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.) solution of oxalyl chloride (1.06 mL, 12.11 mmol) in dichloromethane (10 mL) was added dimethyl sulfoxide (1.43 mL, 20.18 mmol) dropwise. After stirring the mixture for 10 minutes at −78° C., a suspension of (2S)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3,3-dimethyl-butan-1-ol, 14a, (1.0 g, 4.04 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred for 30 minutes at −78° C. and triethylamine (3.38 mL, 24.22 mmol) was added. The mixture was slowly warmed to 0° C. over 2 hours. The mixture was diluted into aqueous saturated NaHCO3 solution and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-15% EtOAc/CH2Cl2 gradient) to afford 680 mg of the desired product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:28])=O>>[Cl:28][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 1-(4-carboxyphenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (2 g) and thionyl chloride (20 ml) was refluxed for 3 hours, and concentrated in vacuo, giving 1-[4-(chloroformyl)phenyl]-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole. A solution of diethyl malonate (1.4 g) and ethanol (0.3 ml) in diethyl ether (15 ml) was added dropwise to a stirred mixture of magnesium (0.16 g), ethanol (0.2 ml) and carbon tetrachloride (0.36 ml) in diethyl ether (5 ml). The resulting mixture was refluxed for 1 hour. A solution of the above acid chloride in tetrahydrofuran (15 ml) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 1 hour and refluxed for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. A mixture of the residue (4 g), acetic acid (40 ml), and 20% sulfuric acid (20 ml) was refluxed for 3.5 hours and then concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give crystals of 1-(4-acetylphenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH:33][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)nc2)c1C(N)=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)nc2)c1C(N)=O
Reaction time: 18 h
Yield: 6.6 %

Procedure:
0.068 cm3 (0.466 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 23° C. and under an argon atmosphere to 0.11 g (0.424 mmol) of 2-acetylamino-4-(6-aminopyridin-3-yl)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 1 hour at a temperature in the region of 20° C., 0.059 cm3 (0.424 mmol) of triethylamine is added to the medium. The reaction mixture is then stirred for 18 hours at this temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: dichloromethane/methanol (95/5 by volume) and pure ethyl acetate gradient]. After concentrating the fractions under reduced pressure, 0.013 g of 2-acetylamino-4-{6-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]pyridin-3-yl}-1H-pyrrole-3-carboxamide is obtained in the form of a white solid. ES+: m/z=466 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1C=CC(=O)C=C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOCC1
Reactant: Nc1cnnn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=c1ccocc1
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nncc2NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (835 mg) and tetrahydropyran-4H-pyran-4-one (481 mg) in acetic acid (10 mL) was added sodium triacetoxyborohydride (1.53 g), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)], and crystallized from diisopropyl ether to give the title compound as pale-beige crystals (573 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.O>C(OCC)(=O)C.[Fe](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Agent: Cl[Fe]Cl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (2.0 g, 6.7 mmol) in ethyl acetate (8 ml) at 7° C. was added methanesulfonyl chloride (0.52 ml, 6.7 mmol) over 3 minutes. The reaction mixture was stirred for 5 minutes before the dropwise addition of triethylamine (1.92 ml, 13.8 mmol) over 5 minutes. The reaction temperature was allowed to rise to 30° C. and the resulting suspension stirred at this temperature for two hours. Iron (II) chloride (8 mg) was then added and the mixture heated at reflux for 40 minute s before the addition of further iron (II) chloride (5 mg) and heating at reflux for 6 hours. The reaction mixture was then cooled to room temperature and water was added (5 ml). The phases were separated and the aqueous phase re-extracted with ethyl acetate. The organic extracts were combined, washed with water (5 ml) and evaporated in vacuo to give an orange-brown solid. The solid was triturated with isohexane (25 ml), the mixture filtered, the filter cake washed with isohexane (2×10 ml) and dried to give the title compound as a dull orange solid (1.06 g, 56%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][OH:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:41]>Cl.O1CCOCC1>[ClH:41].[ClH:41].[NH:8]1[CH2:9][CH2:10][CH:11]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][OH:21])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: ClCCl
Reactant: OCC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: OC[C@@H]1CCCN1C1CCNCC1
Reaction time: 1 h

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol), S)-1-pyrrolidin-2-yl-methanol (0.6 g, 6 mmol), acetic acid (0.3 ml, 6 mmol) in CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.2 g, 6 mmol). The reaction was stirred for 1 h after which time it was washed with saturated sodium hydrogen carbonate, dried with sodium sulphate and concentrated. The residue (1.1 g, 4 mmol) was redissolved in 4M hydrochloric acid in dioxane (6 ml) and stirred for 1 h. Concentration afforded the title compound (1.0 g, quant) as a light orange foam. MS: 185.1 (MH+).