Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]([CH2:18][NH2:19])[OH:17]>O1CCOCC1>[OH:17][CH2:16][CH2:18][NH:19][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: NCCO
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1

Procedure:
A mixture consisting of 4.9 gm., 0.02 mole, of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, 3.0 gm., 0.05 mole, of ethanolamine, and 50 ml. of p-dioxane is stirred at room temperature for twenty-four hours. The precipitate is collected, washed with aqueous sodium bicarbonate solution, dried and recrystallized from methanol to give the pure compound melting at 208°-209° C. Working up the mother liquors gives additional material, the total yield being 3.4 gm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH2:5]O.P(Br)(Br)[Br:16]>C1COCC1>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH2:5][Br:16]
Reactant: BrP(Br)Br
Reactant: COc1cc(C)c(OC)c(CO)c1C
Solvent: C1CCOC1
Product: COc1cc(C)c(OC)c(CBr)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 208.4 %

Procedure:
To a solution of 2,5-dimethoxy-3,6-dimethylbenzyl alcohol (23.6 g, 0.12 mol) in THF (250 ml) was added dropwise phosphorus tribromide (5.7 ml, 0.06 mol) at 0° C., the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (250 ml), and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 32.4 g of 2,5-dimethoxy-3,6-dimethylbenzyl bromide. The resultant bromide was dissolved in acetonitrile (50 ml) and added dropwise to a solution of sodium cyanide (7.35 g, 150 mmol) in water (75 ml) and acetonitrile (75 ml), and the mixture was stirred at room temperature for 3 days. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. It was purified by silica gel chromatography with a small amount of silica gel and eluted with ethyl acetate, and the solvent was removed under reduced pressure. The residue was suspended in hexane, and crystals were filtered to obtain 23.5 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)C.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:17]2[N:16]=[C:15]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:22])[CH:11]=[CH:10][CH:9]=3)=[O:14])[CH:20]=[CH:19][CH:18]=2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: O=C(O)Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
The pyridyl bromide (77)(44 mg, 0.12 mmol) was coupled to 3,5-dichloro-phenylboronic acid (20 mg, 0.10 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The solid was further purified by preparative HPLC to give the title compound.
Reaction SMILES: C1(C[N:8]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[NH:11][C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)C=CC=CC=1.[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[N:33]1([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[NH:8][C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]2=3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrCCCCCCN1CCCCC1
Reactant: O=C1c2ccccc2Nc2ncccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2N(CCCCCCN2CCCCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
24.1 g (0.08 mol) of 5,11-dihydro-5-(phenylmethyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p. 152°-154° C.) were dissolved in 180 ml of anhydrous dimethylformamide, then 2.88 g (0.096 mol) of an 80% sodium hydride dispersion in mineral oil were added at ambient temperature and the resulting mixture was stirred for 45 minutes at 60° C. Then 23.8 g (0.096 mol) of 1-bromo-6-(1-piperidinyl)hexane were added dropwise and the mixture was heated to 120° C. for 30 minutes. After evaporation in vacuo, the residue was partitioned between dichloromethane and 5% aqueous hydrochloric acid, the aqueous phase was separated off and made alkaline with sodium hydroxide. The oil separated was taken up in dichloromethane, the solvent was distilled off in a water jet vacuum, the oily, highly viscous residue was carefully stirred with 250 g of 100% orthophosphoric acid and 7.5 g of phenol and the resulting mixture was heated to 120° C. for 3 hours. The mixture cooled to 70° C. was stirred into 2 kg of crushed ice, then made significantly alkaline by the addition of caustic soda and extracted exhaustively with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was digested with 10 ml of boiling ether and filtered while hot. The ether was evaporated off, the residue was purified by chromatography on silica gel (Macherey-Nagel, 0.2-0.5 mm) using dichloromethane/methanol/cyclohexane/ethyl acetate/conc. ammonia 59/7.5/7.5/25/1 (v/v/v/v/v) as eluant. By evaporating the appropriate fractions and subsequent recrystallisation from acetonitrile, colourless crystals with a melting point of 131°-132° C. were obtained in a yield of 21.8 g (72% of theory) which were found, according to their mixed melting point, thin layer chromatogram, IR, UV., 1H-NMR spectra, to be totally identical to a preparation prepared according to Example 6.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOC(C)=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:29])=[N:3][C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1nc(NC(=S)Nc2ccccc2)c(F)cn1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous tetrahydrofuran (THF; 3 mL) was added sodium hydride (NaH; 0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of phenyl isothiocyanate (1.0 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction mixture was diluted with EtOAc (25 mL), and the resulting solution was washed with satd aq ammonium chloride (NH4Cl; 15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from methanol (MeOH) and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-phenylthiourea as a light yellow solid (0.025 g, 8%): mp 205-208° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (dd, J=3.7, 1.1 Hz, 1H), 10.87 (m, 1H), 8.65 (m, 1H), 8.10 (d, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 7.71 (m, 2H), 7.45 (m, 2H), 7.34 (m, 2H), 7.10 (m, 1H); ESIMS m/z 405 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1)=[O:42]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(N)cc2)c2ccccc12
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)n(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
Into a dry reaction vessel, methyl 2-[1-(4-aminobenzyl)-2-methyl-1H-indol-3-yl]acetate (260 mg, 0.843 mmol) was added, and dissolved in 10 mL dichloromethane. Triethylamine (0.36 mL, 2.59 mmol) was added, and 2-naphthoyl chloride (195 mg, 1.02 mmol) was added slowly in an ice bath. Upon completion of addition, it was reacted for 1 h in an ice bath, and stirred at room temperature for 3 days. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 150 mg, at a yield of 38.4%.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[C:25]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:34][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(OCc2ccc(C(=O)O)cc2)c2ccccc2n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1cc(OCc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
4-[(2-Propylquinolin-4-yloxy)methyl]benzoic acid (240 mg) was added to a mixture of benzene sulphonamide (120 mg), 4-dimethylaminopyridine (90 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (150 mg) in dichloromethane (20 ml) and the mixture stirred overnight. Chloroform (20 ml) was added the mixture was washed successively with 1M citric acid solution (10 ml), water (2×10 ml), saturated sodium chloride solution (5 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue triturated with methanol to give 4-[(2-propylquinolin-4-yloxy)methyl]-N-phenylsulphonylbenzamide as a white powder (160 mg), m.p. 140° C. (dec.); NMR (d6 -DMSO): 0.95(t,3H), 1.79(m,2H), 2.88(t,2H), 5.5(s,2H), 7.14(s,1H), 7.5-7.7(m,6H), 7.78(dt,1H), 7.87-8.02(m,5H), 8.18(dd,1H); mass spectrum (-ve FAB, DMSO/Gly): 495 (M-H)- ; microanalysis found: C,66.1; H,5.4; N,5.8%; C26H24N2O4S.0.5H 2 O requires: C,66.5; H,5.3; N,6.0%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CC#N.Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:17][C:16]([OH:19])=[O:18]
Reactant: N#CCc1ccccc1OC(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccccc1OC(F)(F)F

Procedure:
2-Trifluoromethoxyphenylacetonitrile (0.49 g, 2.6 mmol) from Step 3 above was refluxed for 3 h in a 1:1 mixture of acetic acid and concentrated aqueous HCl. The solvents were removed under reduced pressure. The residue was partitioned between EtOAc (75 mL) and water (2×25 mL). The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure to give 2-trifluoromethoxyphenylacetic acid as an amorphous solid (HPLC retention time=6.8 min (method A)).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(#N)C>[C:14]([N:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2)(=[O:16])[CH3:15]
Reactant: O=C1CCNc2ccccc2CN1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)N1CCC(=O)NCc2ccccc21
Temperature: 80 °C

Procedure:
2,3,5,6-Tetrahydro-1H-benzo[b][1,5]diazocin-4-one (prepared as in J. Am. Chem. Soc. 2004, 126, 3529-3533) (1.00 g, 5.68 mmol) was dissolved in anh acetonitrile (50 ml). Acetic anhydride (587 μL, 6.25 mmol) was added and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated, triturated with ether, and filtered to afford title compound as a beige solid. (1.063 g, 86%) mp 236-239° C.; LCMS: m/z=219.30 (M+H+), HPLC (95% purity); 1H NMR (400 MHz, DMSO-d6) δ 7.82 (m, 1H), 7.38 (m, 4H), 4.64 (m, 1H), 4.29 (m, 1H), 3.87 (m, 1H), 2.92 (m, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 1.69 (s, 3H).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>ClCCl>[CH3:25][O:24][C:22]([CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[O:23]
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: COC(=O)CCS
Solvent: ClCCl
Product: COC(=O)CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (122 mg) was dissolved in dichloromethane (8 ml) and then methyl 3-mercaptopropionate (0.05 ml) was added. The red-brown solution became yellow-green immediately after addition of the thiol. The solution was stirred at room temperature for 5 hours. Removal of the solvent and recrystallisation of the residue from hexane gave the product (107.5 mg, 78%) as yellow needles, melting point 92°-94° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:21])=[O:34])=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CS(=O)CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 34 from 5-((3,5-dichloropyridin-4-yl)thio)-N-(3-(methylthio)propyl)-4-nitrothiophene-2-carboxamide (100 mg, 0.23 mmol) and MCPBA (198 mg, 1.15 mmol). The titled product was obtained as a white solid (72.0 mg, 69% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.93 (1H, m), 8.41 (1H, s), 3.30 (2H, m), 2.80 (1H, m), 2.64 (1H, m), 2.50 (3H, s), 1.84 (2H, m). MS m/z: 454.08, 456.08 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.Cl[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7].[Cl-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7]
Reactant: CNC
Reactant: O=C(Cl)N1CCNC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCNC1=O

Procedure:
A mixture of 50 parts by volume of a 50% strength aqueous dimethylamine solution and 70 parts by volume of tetrahydrofurane was adjusted to pH = 8 with 5 N hydrochoric acid. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were added gradually thereto while stirring and cooling with ice and the pH value was maintained by simultaneous addition of further dimethylamine solution. The mixture was further stirred until the pH was constant, the tetrahydrofurane was then stripped off and the residue was saturated with sodium chloride and repeatedly extracted with ethyl acetate. The organic solution was washed and saturated sodium chloride solution, dried over MgSO4 and filtered, and the solvent was evaporated off. The residue was recrystallized from acetone and dried in a vacuum desiccator over P2O5.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=C.ClCCl.[BH4-].[Na+].C[OH:29]>>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH2:1][CH2:2][OH:29])[NH:8][N:7]=1
Reactant: CO
Reactant: C=CCc1[nH]nc(-c2ccc(C)cc2F)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCO)c2-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazole (1.0 g, 3.42 mmol) was dissolved in methanol (40 mL) and dichloromethane (10 mL) and cooled to −78° C. on a dry-ice/acetone bath. Ozone was bubbled through the solution for 2 h, until the solution appeared light blue. To the reaction added sodium borohydride (0.129 g, 3.42 mmol) slowly. Upon complete addition, the reaction was removed from the dry-ice bath and stirred at room temperature for 1 h. Excess solvent was removed under reduced pressure and the reaction was extracted with EtOAc/H2O, dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (0.70 g). LCMS m/z=297.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 2.79 (t, J=7.20 Hz, 2H), 3.62 (t, J=7.33 Hz, 2H), 6.93-7.00 (m, 1H), 7.09-7.14 (m, 2H), 7.15-7.23 (m, 3H), 7.25-7.31 (m, 2H), 12.86 (bs, 1H).
Reaction SMILES: Cl.C([NH:6][S:7]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][C:27](C)=[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[C:29]=3[CH2:30][OH:31])=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])(C)(C)C.[NH3:43].CO>C(O)C>[OH:31][CH2:30][C:29]1[C:24]([CH2:23][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7](=[O:9])(=[O:8])[NH2:6])=[CH:17][CH:18]=2)=[CH:25][N:26]=[CH:27][C:28]=1[O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH2:41])=[NH:43]
Reactant: N
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1OCc1cccc(C#N)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)c1cccc(COc2cncc(CNc3ccc(-c4ccccc4S(N)(=O)=O)cc3)c2CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 4′-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-2-sulfonic acid tert-butylamide (13) (100 mg, 0.17 mmol) in absolute ethyl alcohol (30 mL) at 0° C. for 30 minutes. The septum was replaced and the reaction mixture was stirred at room temperature overnight. Hydrogen chloride gas was purged with nitrogen gas for 2 hours and the solvent evaporated to give the crude amide ester as a solid. Ammonia in methyl alcohol (30 mL, 7 M, 350 mmol) was added to the crude amide ester and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the product purified on a silica gel column using a mixture of dichloromethane:methyl alcohol (4:1) as eluant to give the corresponding 3-{4-hydroxymethyl-5-[(2′-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-yloxymethyl}-benzamidine (14) (90 mg, 97% yield) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OB(O)c1ccccc1Cl
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccccc1Cl
Yield: 18 %

Procedure:
Prepared in 18% yield from 2-chloro-3-cyanopyridine and 2-chlorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 215.0 (M+H)+; 1H NMR (CDCl3) δ 7.41-7.49 (m, 4H), 7.53-7.56 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.489 g, 3.40 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.896 mL, 3.40 mmol) dissolved in water (1.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.209 mL, 3.40 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (17.59 mL, 105.54 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.594 g, 42.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.82-1.89 (m, 1H), 2.08-2.16 (m, 1H), 2.19-2.27 (m, 1H), 2.32-2.38 (m, 1H), 3.04-3.11 (m, 1H), 3.34-3.41 (m, 1H), 3.68 (s, 3H), 4.09-4.15 (m, 1H), 5.04-5.08 (m, 1H), 5.57 (s, 1H), 6.80 (d, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:7][CH:8]=1.[O:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([CH2:2][NH:1][C:27]([CH:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[O:28])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
To a mixture of 5-(aminomethyl)-N-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (103 mg) and dichloromethane (2 mL) were added tetrahydro-2H-pyran-4-carboxylic acid (53 mg), 1-hydroxybenzotriazole (69 mg), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg) in this order at room temperature, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained product was solidified from a mixed solvent of ethanol and ethyl acetate to obtain N-({2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)tetrahydro-2H-pyran-4-carboxamide (41 mg) as a colorless powder.