Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:23]1[CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:7]=2)[CH:20]=[CH:21][C:22]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (120 mg, 0.212 mmol) and isobutylamine (1.1 mL, 11 mmol) the title compound was obtained as a light orange solid (94 mg, 0.16 mmol, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (br. s., 1H), 7.83-8.30 (m, 1H), 7.43-7.71 (m, 3H), 7.30-7.43 (m, 3H), 7.15-7.30 (m, 1H), 5.97-6.36 (m, 1H), 3.73-4.07 (m, 2H), 3.47 (t, J=11.0 Hz, 2H), 3.20-3.31 (m, 1H), 2.94-3.16 (m, 2H), 1.93-2.08 (m, 2H), 1.61-1.89 (m, 3H), 0.75-0.93 (m, 6H). MS (ESI): 604.19 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC(O)C(O)C.O>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>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[C:7]#[N:8])([CH3:13])[CH3:12]
Reactant: OB(O)c1cccs1
Reactant: CC(C)Oc1ccc(Br)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)Oc1ccc(-c2cccs2)cc1C#N
Yield: 81.7 %

Procedure:
A microwave vial was charged with 5-bromo-2-isopropoxybenzonitrile (200 mg, 0.83 mmol), thiophen-2-ylboronic acid (106.5 mg, 0.83 mmol), potassium carbonate (345.3 mg, 2.49 mmol) and 3:1 mixture of dimethylethylene glycol/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirred solution for 10 min. Pd(PPh3)4 (20.4 mg, 0.02 mmol) was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and dried over MgSO4. The product was purified chromatography (EA/hexanes) to afford 165 mg (82%) of 2-isopropoxy-5-(thiophen-2-yl)benzonitrile TRIO INT-1 as colorless oil. LCMS-ESI (m/z) calculated for C14H13NOS: 243.1; found 266.0 [M+Na]+, tR=3.90 min. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=2.3 Hz, 1H), 7.69 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.19 (dd, J=3.6, 1.1 Hz, 1H), 7.05 (dd, J=5.1, 3.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.65 (dt, J=12.2, 6.1 Hz, 1H), 1.43-1.37 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:15](=O)[CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:20]O>N1C=CC=CC=1>[CH2:16]([C:15]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:11]([CH2:12][CH3:13])[O:14][N:20]=1)[CH3:17]
Reactant: CCC(=O)C(Cc1ccc(OC)cc1)C(=O)CC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1Cc1ccc(OC)cc1

Procedure:
3,5-Diethyl-4-[(4-methoxyphenyl)methyl]isoxazole [I; Ar is 4-CH3OC6H4, Y is CH2, R is C2H5 ] was prepared from 41.1 g. of 4-(4-methoxyphenylmethyl)-3,5-heptanedione and 12.0 g. of hydroxylamine hydrochloride in 100 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a colorless oil, b.p. 145°-146° C. (0.1 mm.); MIC=25 μg/ml (herpes 2).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:30][N:29]([C:31]([C:33]3[O:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:36][N:37]=3)=[O:32])[CH2:28]2)[CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH:27]3[CH2:28][N:29]([C:31]([C:33]4[O:34][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[N:36][N:37]=4)=[O:32])[CH2:30]3)=[CH:25][C:18]=2[O:17][CH3:16])[CH2:8][O:9]1
Reactant: COc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Reactant: C1CNC2(C1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCCC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.111 g, ca. 70%, 0.34 mmol) and 2-methoxy-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.13 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was then added, followed by sodium triacetoxyhydroborate (0.145 g, 0.69 mmol). The mixture was stirred at ambient temperature overnight. LC-MS showed some remaining starting material. An additional amount of sodium triacetoxyhydroborate (0.11 g) was added and stirring was continued for 6 hours. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a colourless residue, which was was purified by preparative reverse-phase HPLC at pH 10 to give 0.113 g (69%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.58-1.66 (m, 2H), 2.07-2.12 (m, 2H), 2.55-2.58 (m, 2H), 3.81 (s, 3H), 3.88 (s, 2H), 4.08-4.12 (m, 1H), 4.44 (d, 2H), 4.54-4.58 (m, 1H), 4.64 (ddd, 1H), 4.79 (d, 2H), 5.10 (ddd, 1H), 5.19 (ddd, 1H), 6.42 (dd, 1H), 6.54 (d, 1H), 7.20 (d, 1H), 7.64-7.72 (m, 3H), 8.05-8.11 (m, 2H). MS (APCI+) m/z 477.2 [M+H]+, LC purity: 93%
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][C:41](N2CCSC2=S)=[O:42])[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][C:41]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:42])[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Reactant: COCCOCOc1ccc(C=CC(=O)N2CCSC2=S)cc1OC
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 94 %

Procedure:
To a solution of 620 mg (2 mmol) of the piperazine derivative in dry tetrahydrofuran (5 ml) was added a solution of 766 mg (2.0 mmol) of N-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl) thiazolidine-2-thione in dry tetrahydrofuran (5 ml), and the mixture was allowed to react at room temperature overnight under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with N'chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous scdium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol ((50 : 1), to give 1.08 g (1.88 mmol) of N-[3-[3-methoxy-4-(β-methoxyethoxymetoxy) phenyl]-2-propenoyl]-N'-(3-benzhydroxypropyl)-piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.O.[F:18][C:19]([F:23])([F:22])[CH:20]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:20]2[C:19]([F:23])([F:22])[F:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Reactant: O=CC(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-n2c(C(F)(F)F)nc3cnccc32)cc1

Procedure:
A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (420 mg, 2.0 mmol) (prepared as above), trifluoroacetaldehyde hydrate (232 mg, 2.0 mmol), and sodium metabisulphite (475 mg, 2.5 mmol) in N,N-dimethylacetamide (10 ml) was heated under reflux for 16 hours. After being cooled, the mixture was diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (50 ml) and water (5×50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate) to give 1-(4-cyanophenyl)-2-trifluoromethylimidazo[4,5-c]pyridine, 337 mg.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:17]=[C:16](F)[CH:15]=[C:14]([F:19])[N:13]=1.O>CO.CN1CCCC1=O>[NH2:11][C:12]1[N:13]=[C:14]([F:19])[CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:17]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Nc1nc(F)cc(F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Nc1nc(F)cc(Oc2ccc(Cl)cc2)n1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
2.52 g (0.038 mol) of 85% sodium hydroxide were dissolved in 50 ml of methanol, 4.9 g (0.0382 mol) of 4-chlorophenol were added, and the mixture was evaporated to dryness. The residue of salt obtained in this way was taken up in 50 ml of N-methyl-2-pyrrolidone and, at 25° C., 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine were added, and the mixture was stirred at 140° C. for 4 hours. After the reaction mixture had been cooled to 25° C. it was stirred into 500 ml of water, and the resulting precipitate was isolated. 7.4 g (81% of theory) of the title compound of melting point 223°-226° C. were obtained in this way.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][N+:28]#[C-:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Na+]>CS(C)=O.C(OCC)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2][C:27]([N+:28]#[C-:29])([S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:30])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [C-]#[N+]C(CCCC(C)(C(=O)OCC)c1ccccc1)(CCCC(C)(C(=O)OCC)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 117.8 %

Procedure:
To a solution of ethyl 5-bromo-2-methyl-2-phenyl-pentanoate (25 g, 75.25 mmol), tetra-ii-butylammonium iodide (2.78 g, 7.53 mmol), and p-toluenesulphonylmethyl isocyanide (TosMIC, 7.34 g, 37.63 mmol) in anhydrous DMSO (400 mL) and anhydrous diethyl ether (I150 mL) was added sodium hydride (60% dispersion in mineral oil, 3.80 g, 95 mmol) at rt under N2 atmosphere. The reaction mixture was stirred for 24 h at rt, then carefully hydrolized with ice-water (600 mL), and extracted with diethyl ether (2×300 mL). The organic layer was washed with brine (2×300 mL) dried over anhydrous MgSO4, concentrated in vacuo to furnish crude 2,10-dimethyl-6-isocyano-6-(4-tolyl-sulfonyl)-2,10-diphenyl-undecanedioic acid diethyl ester (28 g) as a brown oil. A solution of this crude intermediate (25 g) was dissolved in CH2Cl2 (500 mL) and concd. HCl (140 mL) and stirred for 2 h at rt. The reaction mixture was diluted with water (500 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined layers were washed with saturated NaHCO3 solution (150 mL), and brine (150 mL), dried over MgSO4, and concentrated ill vacuo. The resulting crude oil was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/20, 1/10) to furnish 2,10-dimethyl-6-oxo-2,10-diphenyl-undecanedioic acid diethyl ester (9.5 g, 50.3%) as a light yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.40-7.10 (m, 10H), 4.20-4.05 (m, 4H), 2.38 (m, 4H), 2.05-1.80 (m, 4H), 1.60 (s, 6H), 1.50-1.20 (m, 4H), 1.22 (m, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 210.24, 176.06, 143.71, 128.42, 126.72, 125.97, 60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13. HRMS (LSIMS, nba): Calcd. for C29H39O5 (MH+): 467.2797, found: 467.2772.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:22]3)=[O:16])[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2cccc(Br)c2)c(C)c1C(=O)O
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Yield: 61 %

Procedure:
In analogy to the procedure described in example 12D], 1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 61% yield as brown viscous oil. MS: 419.2 (MH+, 1 Br).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61F and ethyl 5-bromovalerate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1=NC2(CCOc3ccc(-c4cc(F)cc(F)c4)cc32)N=C1N
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (Intermediate 4, 0.10 g, 0.34 mmol), 3,5-difluorophenylboronic acid (0.11 g, 0.68 mmol) and 2 M K2CO3 (aq., 0.34 mL, 0.69 mmol) were mixed in dioxane (3 mL) and degassed by passing through nitrogen for 5 min. Then (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (14 mg, 20 μmol) was added and the mixture was heated in a microwave oven at 130° C. for 1 h. Purification by preparative chromatography gave the title compound (17 mg, 15% yield): 1H NMR (400 MHz, CDCl3) δ ppm 2.25 (m, 2H), 2.41 (s, 3H), 4.57 (m, 2H), 6.66-6.86 (m, 2H), 6.89-7.05 (m, 3H), 7.38 (d, 1H), 8.1-9.0 (br m, 2H); MS (ES+) m/z 328 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[Cl:1][C:2]1[C:11](/[CH:12]=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: Cc1c(F)ccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Yield: 86.1 %

Procedure:
Following the procedure for Intermediate 22, 2-chloro-7-fluoro-8-methyl-quinoline-3-carbaldehyde (6.6 g, 29.5 mmol), titanium(IV) isopropoxide (17 g; 60 mmol), (R)-(−)-2-methyl-2-propanesulfinamide (3.6 g, 29.5 mmol) and THF (200 mL) gave the title compound (8.3 g, 86%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.73 (1H, s), 7.71 (1H, dd, J=6.0 Hz), 7.40 (1H, t, J=8.2 Hz), 2.69 (3H, s), 1.32 (9H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH2:28][O:29][CH3:30])[CH2:23]3)[C:7]=2[C:6]=1[CH3:33])=O.[NH3:34]>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:33])=[C:5]([C:3]([NH2:34])=[O:2])[S:32][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH2:28][O:29][CH3:30])[CH2:23]2)[CH:16]=1
Reactant: N
Reactant: COCC(=O)N1CCC(Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)OC)c(C)c23)C1
Solvent: CO
Product: COCC(=O)N1CCC(Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[1-(2-methoxy-acetyl)-pyrrolidin-3-yloxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and ammonia in methanol.
Reaction SMILES: [C:1]([C:7]1[S:8][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][N:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO.[Pd]>[CH2:1]([C:7]1[S:8][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ncc(S(N)(=O)=O)s1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1ncc(S(N)(=O)=O)s1
Reaction time: 48 h
Yield: 80.5 %

Procedure:
2-(1-hexynyl)-5-thiazole sulfonamide (0.04 g, 0.16 mmol) was dissolved in 5 mL of methanol. 0.01 g of palladium/carbon was added and the solution purged three times with hydrogen. The reaction was left under 30 psi of hydrogen for 48 hours. The mixture was filtered through celite and the filtrate concentrated. The residue was purified on the chromatatron (eluted with 5:1.5:3.5 CH2Cl2 /Et2O, hexane) to afford 32 mg (80%) of 2-hexyl-5-thiazole sulfonamide.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:23])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:20][CH2:21][CH3:22])=[N:14][CH:15]=[C:16]([C:18]#[CH:19])[CH:17]=3)=[N:7][C:6]=12.[OH:24]S(O)(=O)=O>CC(C)=O>[C:18]([C:16]1[CH:17]=[C:12]([C:8]2[NH:9][C:10](=[O:11])[C:5]3[C:6](=[C:2]([Br:1])[N:3]([CH3:23])[N:4]=3)[N:7]=2)[C:13]([O:20][CH2:21][CH3:22])=[N:14][CH:15]=1)(=[O:24])[CH3:19]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1cnc(OCC)c(-c2nc3c(Br)n(C)nc3c(=O)[nH]2)c1
Solvent: CC(C)=O
Product: CCOc1ncc(C(C)=O)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Reaction time: 14 h

Procedure:
A mixture of 3-bromo-5-(2-ethoxy-5-ethynyl-3-pyridinyl)-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 57) (750 mg, 2 mmol), 1N H2SO4 (2 mL) and HgSO4 (50 mg, 0.17 mmol) in acetone (25 mL) was stirred at reflux for 10 h then at room temperature for 14 h. Further H2SO4 (5 mL of 1 N) was added and refluxing was continued for a further 4 h. The mixture was cooled and the solvent evaporated and the residue partitioned between dichloromethane and water. After basifying with solid sodium bicarbonate a white precipitate formed which was filtered off before separating the phases. The organic layer was dried (MgSO4), concentrated and combined with the solid previously filtered to give the title compound as a poorly soluble solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:14][N:13]([C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH2:12]1)#[N:9].Br[C:47]1[C:48]([CH2:52][OH:53])=[N:49][NH:50][CH:51]=1>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:32]2[CH:36]=[C:35]([C:47]3[C:48]([CH2:52][OH:53])=[N:49][NH:50][CH:51]=3)[CH:34]=[N:33]2)[CH2:12][N:13]([C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:24])[F:25])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH2:14]1)#[N:9]
Reactant: OCc1n[nH]cc1Br
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4c[nH]nc4CO)cn3)C2)cc1F)C(F)(F)F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and (4-bromo-1H-pyrazol-3-yl)methanol. LCMS calculated for C22H21F5N7O2 (M+1)+: m/z=510.2. Found: 510.0.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
1.7 mL of trifluoroacetic acid was added to 0.17 g of tert-butyl 4-phenethyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration. Ethyl acetate and water were added to the obtained solid substance and pH was adjusted to pH 6.8 with a saturated sodium hydrogen carbonate aqueous solution. A solid substance was separated by filtration to obtain 65 mg of 4-phenethyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoic acid as white solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([OH:17])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: O[C@@H]1CCCOC1
Product: O=[N+]([O-])c1cccnc1O[C@@H]1CCCOC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and (R)-tetrahydro-pyran-3-ol.