Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH:14][S:15]([C:18]1[N:22]=[C:21]([NH2:23])[NH:20][N:19]=1)(=[O:17])=[O:16].[C:24](OC)(=[O:30])[CH2:25][C:26](OC)=[O:27]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[NH:14][S:15]([C:18]1[N:22]=[C:21]2[N:23]=[C:24]([OH:30])[CH:25]=[C:26]([OH:27])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cccc(C(F)(F)F)c1NS(=O)(=O)c1n[nH]c(N)n1
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C(F)(F)F)c1NS(=O)(=O)c1nc2nc(O)cc(O)n2n1
Reaction time: 48 h

Procedure:
Sodium (5.90 g, 257 mmol) was added to 250 ml of absolute ethanol under nitrogen and allowed to react. A 28.67 g, 85.0 mmol sample of N-(2-methoxy-6-trifluoromethylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 24.46 g (170 mmol) of dimethyl malonate were added and the mixture heated at reflux with stirring for two days. It was then cooled with an ice bath and the solids present were collected by filtration and washed with hexane. They were then dissolved in about 150 ml of ice water and acidified with conc. hydrochloric acid to obtain 11.95 g, the title compound, which was collected by filtration and dried. The ethanolic solution was concentrated by evaporation and dried by adding toluene and removing volatiles by evaporation under reduced pressure three times. The residue was taken up in ethanol and treated as before with sodium and 16.85 g of dimethyl malonate to obtain another 10.26 g of the title compound. A total of 22.21 g (64.5 percent of theory) of the title compound, which melts at 237°-243° C. with decomposition, was obtained.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Sn](=O)CCCC)CCC.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>C1(C)C=CC=CC=1>[CH2:2]([C:1]1[NH:24][N:23]=[N:22][N:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCCc1nnn[nH]1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of hexanenitrile (938 mg, 9.65 mmol), dibutyltin oxide (293 mg, 0.98 mmol) and 97% trimethylsilylazide (2.60 mL, 19.1 mmol) in toluene (20 mL) were heated at ~110° C. for 25 hours and ambient temperature for one hour. The reaction mixture was extracted with 1M sodium hydroxide solution (4×10 mL) and the combined aqueous extracts were acidified with 6M hydrochloric acid to pH 3-4 and extracted with 10% isopropanol in chloroform (3×10 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 950 mg (70%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ0.87 (t, J=7 Hz, 3H), 1.30-1.45 (m, 4H), 1.90 (pentet, J=7 Hz, 2H), 3.12 (t, J=7 Hz, 2H). 13C NMR (CDCl3, 75 MHz) 13.70, 22.06, 23.35, 27.31, 31.05, 156.97. IR (CDCl3) 2900, 1555 cm-1. MS (DCl/NH3) m/e 141 (M+H)+, 158 (M+H+NH3)+. Anal calcd for C6H12N4 : C, 51.41; H, 8.63; N, 39.97. Found: C, 51.25; H, 8.59; N, 39.93.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.Br.Br.[NH:13]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1F
Reactant: OC1CNCCNC1
Agent: Br
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)nc1N1CCNCC(O)C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.660 mmol; 547.9 mg), 1,4-diazepan-6-ol dihydrobromide (3.989 mmol; 1109 mg), and N,N′-diisopropylethylamine (10.64 mmol; 1389 mg; 1.87 mL) in Isopropanol (10 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated. The residue was purified on silica eluted with 0 to 10% MeOH in DCM to afford 1-(6-bromo-3-methoxy-2-pyridyl)-1,4-diazepan-6-ol (301.2 mg, 37%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: Cn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
A solution of NaHMDS in THF (1.0 M, 1.05 mL, 1.05 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (277 mg, 1.05 mmol) in DMF (14 mL) at room temperature. After 18 minutes, a suspension of 6-chloro-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.04 (237 mg, 0.967 mmol) in DMF (4 mL) was added and mixture stirred at room temperature. After 40 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water and extracted with ethyl acetate (3×50 mL). Combined organics were washed with 50% Brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. This residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1ccccc1-c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(-c2ccccc2C)cc1

Procedure:
The phenol from step A (1.72 g, 9.35 mmol), CS2CO3 (3.6 g, 10.5 mmol) and allylbromide (0.9 mL, 10.3 mmol) in DMF (47 nmL) were stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc, washed with water (3×), brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH:14]=1)[NH2:13].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].O>CN(C=O)C>[NH2:13][C:12]1[CH:14]=[C:8]([S:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
14.1 4.25 g (30.7 mmol) of potassium-carbonate are added to a solution of 2.65 g (15.4 mmol) of 5-chloro-2-nitroaniline and 1.66 g (1 5.4 mmol) of methyl thioglycolate in 14 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is introduced into water, and the resultant precipitate is filtered off, giving methyl (3-amino-4-nitrophenylsulfanyl)acetate as a yellow solid; ESI 243.
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[C:8]1([CH2:18][C:19]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27](OC)=O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C>[CH3:4][C:3]1[N:5]=[C:27]([C:23]2[S:24][CH:25]=[CH:26][C:22]=2[NH:21][C:19](=[O:20])[CH2:18][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[O:7][N:6]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n1
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion, 15 mg, 0.39 mmol) was added to a solution of acetamide oxime (29 mg, 0.39 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 10 minutes after which a solution of methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (107 mg, 0.33 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 h and was subsequently diluted with ethyl acetate (10 mL). The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered and concentrated under vacuum. The residue was dissolved in THF (1 mL) and HCl (1 mL of a 10% aqueous solution) was added. The mixture was stirred for 20 minutes after which ethyl acetate (10 mL) was added. The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified by preparative HPLC to give N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Retention time (min)=9.533, method [7], MS (ESI) 350.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 8.03 (d, J=9.3 Hz, 2H), 7.59-7.49 (m, 5H), 4.27 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:44]1[CH:49]=[CH:48][N:47]=[CH:46][C:45]=1[C:50](Cl)=[O:51]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:50]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][N:44]=4)=[O:51])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.085 g, 0.00021 mol) in dry N,N-Dimethylformamide (1.00 mL, 0.0129 mol) was added N,N-Diisopropylethylamine (0.1120 mL, 0.0006430 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0508 g, 0.000356 mol) stirred at 0° C. for 30 minutes. The reaction mixture was filtered and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.95 (dd, J=8.4, 1.3, 1H), 8.81 (dd, J=7.1, 2.5, 1H), 8.75 (d, J=3.9, 1H), 8.68 (d, J=15.6, 1H), 8.17 (dd, J=43.7, 8.7, 2H), 7.48 (dd, J=25.1, 8.8, 2H), 6.18 (dt, J=11.1, 5.6, 1H), 4.85 (d, J=18.5, 1H), 4.72 (d, J=7.4, 1H), 4.11 (d, J=5.5, 1H), 3.88 (d, J=9.3, 1H), 3.78-3.54 (m, 6H), 3.43 (t, J=12.3, 1H), 3.11 (dq, J=14.5, 7.2, 2H), 2.76 (s, 2H), 1.26 (d, J=6.6, 3H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Nc1ccc(Br)nc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2cc(-c3ccc(N)cn3)ccc21
Temperature: 110 °C

Procedure:
In a 10-20 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (250 mg, 1.34 mmol) and the 6-bromopyridin-3-amine (250 mg, 1.34 mmol) were dissolved in dioxane (7 mL) and water (1.5 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min and then potassium carbonate (368 mg, 2.67 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 3 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-75% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C13H12N4: 225.1 (M+H+); found: 225.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[O:36][N:35]=[C:34]([CH3:37])[CH:33]=5)[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)on1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K84) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (33 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:13]([Li])[CH2:14][CH2:15][CH3:16].Cl>CCCCCC>[CH2:13]([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCCCCC
Product: CCCC[PH](=O)C(OCC)OCC

Procedure:
Following the procedure of Example 8, but using 1.96 g of ethyl diethoxymethylphosphinate and 12.5 ml of a 1.6 molar solution of n-butyl lithium in n-hexane and adding 20 ml of 0.1M hydrochloric acid prior to extraction, n-butyl(diethoxymethyl) phosphine oxide is obtained as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)nc1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2F)nc1
Reaction time: 8 h

Procedure:
Place 6-(2-fluoro-4-formylphenoxy)nicotinamide (Example 223, step 1) (0.700 g, 2.69 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.348 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (13.5 mL), cap and stir overnight. Add NaBH4 (0.204 g, 5.38 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate it. Purify by chromatography eluting with 0% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 1 hour at 20 mL/min to give 6-(2-fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide. (0.717 g, 71.3%). Dissolve the compound in dichloromethane: methanol (10 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.904 g): TOF MS ES+ 374.2 (M+H)+, HRMS calcd for C20H25N3O3F 374.1880 (M+H)+, found 374.1881, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=8.7 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:19]=[CH:18][C:17]=1[NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:31][C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=3)=[CH:21][C:16]=2[Cl:15])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1nccc(Oc2ccc(N)c(Cl)c2)n1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)c2)n1
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of 281 mg (1.27 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 5 min. drop by drop at 0° C. to a solution of 340 mg (1.27 mmol) 2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and purified by chromatography on silica (ethyl acetate/isohexane 1:4) to give 162 mg (26%) 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)(=O)=O.[C-:18]#[N:19].[Na+]>CS(C)=O.CCOC(C)=O>[C:12]1([C:10]2[O:9][N:8]=[C:7]([CH2:6][C:18]#[N:19])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Yield: 110.2 %

Procedure:
To a solution of (5-phenylisoxazol-3-yl)methyl methanesulfonate (example 33d) (261 mg, 1.03 mmol) in anhydrous DMSO (8 mL) was added NaCN (252 mg, 5.15 mmol). The reaction mixture was heated at 80° C. under N2 for 15 hours, then diluted with EtOAc and washed with H2O (5×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield a yellow solid (209 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): 4.30 (s, 2H), 7.12 (s, 1H), 7.55-7.57 (m, 3H), 7.89-7.92 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCCc2[nH]cnc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester (18.9 g, 97 mmol, J. Am. Chem. Soc., 1996, 98, 984) in acetonitrile (250 ml) were added triethylamine (27 ml, 194 mmol) and a solution of trityl chloride (40.6 g, 146 mmol) in acetonitrile (500 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate, washed with water (2×) and brine (1×), and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/heptane, to yield 20.8 g (49%) of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester as a colourless solid. From the mother liquor more product (10.3 g, 24%) was isolated by column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1>>[CH:9]1([NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:17]3[C:16]([CH3:15])=[CH:20][C:19]([CH3:21])=[N:18]3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1cncc(NC2CCCCC2)n1
Product: Cc1cc(C)n(-c2cncc(NC3CCCCC3)n2)n1

Procedure:
Was prepared according to Example 3 from (6-chloro-pyrazin-2-yl)-cyclohexylamine and 3,5-dimethylpyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(OCC3CCNC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
1.55 g (4.17 mmol) of tert-butyl 3-(4′-fluorobiphenyl-4-yloxymethyl)pyrrolidine-1-carboxylate are dissolved in 40 ml of dichloromethane and then, at 0° C., 6.00 ml (80.77 mmol) of trifluoroacetic acid are subsequently added. After stirring at ambient temperature for two hours, the mixture is concentrated to dryness and then the residue is taken up in water and dichloromethane. A saturated sodium hydrogencarbonate solution is added and then the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum. 0.98 g of product is obtained in the form of an oil, used as is in the following stage.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.F[B-](F)(F)F.[CH3:15][O+](C)C>>[CH3:1][C:2]1([CH3:9])[CH2:3][C:4]([O:8][CH3:15])=[N:5][CH2:6][CH2:7]1
Reactant: CC1(C)CCNC(=O)C1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NCCC(C)(C)C1

Procedure:
A sample of the title compound of EXAMPLE 168 (636 mg, 5 mmol) was reacted with trimethyloxonium tetrafluoroborate (890 mg, 6 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 550 mg (78%) of the title material.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1>>[OH:1][C:2]1[C:11]([O:12][C:15]2[CH:14]=[C:13]([CH3:22])[CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(O)c1O
Product: COC(=O)c1cccc(Oc2cccc(C)c2)c1O
Yield: 36.5 %

Procedure:
According to the method of (Example 99) <Step 1>, from methyl 2,3-dihydroxybenzoate (1 g) and m-tolyl boronic acid (0.97 g) that are commercially available, the subject compound (0.56 g) was obtained as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]#[C:14][CH:15]([NH:17][OH:18])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[N-:21]=[C:22]=[O:23].[K+]>C(OCC)(=O)C.O>[OH:18][N:17]([CH:15]([C:14]#[C:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:16])[C:22]([NH2:21])=[O:23]
Reactant: [N-]=C=O
Reactant: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)N(O)C(N)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
The N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine prepared in step 3 above was taken up in ethyl acetate (36 kg) and cooled to 5° C. A solution of freshly prepared potassium isocyanate (10 kg) in water (18 kg) was slowly added and the exotherimic reaction was maintained below 10° C. The reaction mixture was agitated for 30 min. The layers were separated and the organic phase was dried over MgSO4 and filtered. The filtrate was diluted with heptane (58 kg) and agitated for one hour. The resulting crude product was filtered, dissolved in 45° C. ethyl acetate (42 kg). PWA carbon (0.5 kg) and Ultra Norit C (0.5 kg) were added and the mixture was agitated for 30 minutes and filtered. The combined filtrate and washings were diluted with heptane (68 kg) and filtered to provide N-hydroxy-N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]urea (2.94 kg). m.p. 139°-40° C.; 1H NMR (d6Me2SO) 1.33 (d, 3, J=7 Hz), 5.10 (q, 1, J=7 Hz), 6.55 (s, 2), 6.87 (m, 1), 7.03 (m, 1), 7.13 (m, 3), 7.25 (t, 2, J=8 Hz), 7.37 (t, 1, J=8 Hz), 9.33 (s, 1) ppm; mass spectrum m/e (rel intensity) 332 (80, M+ +NH4), 315 (75, M+ +H), 289 (80), 272 (100). Analysis calculated for C17 H15FN2O3 : C, 64.95, H, 4.81, N, 8.91; found: C, 64.67, H, 4.76, N, 8.81.