Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:4]1[CH:3]=[C:2]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:9]2=[O:16])[CH:7]=[CH:6][N:5]=1
Reactant: O=C1CCCCCC1
Reactant: Cc1cc(Br)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1cc(C2CCCCCC2=O)ccn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2-methylpyridine (300 mg, 1.744 mmol), cycloheptanone (0.206 mL, 1.744 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (121 mg, 0.209 mmol), Pd2(dba)3 (80 mg, 0.087 mmol), and Cs2CO3 (739 mg, 2.267 mmol) in 2-propanol (1.5 mL) and toluene (1.5 mL) was stirred at 85° C. overnight. After this time, the mixture was filtered through diatomaceous earth, then the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (7:3 hexane-EtOAc, eluant) to afford the title compound. MS (APCI+) m/z 204 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
0.07 g (0.15 mmol) of methyl 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylureido)thiazol-5-yl]phenyl}propanoate is placed in 3 ml of tetrahydrofuran and 0.2 ml (0.2 mmol) of aqueous 1M lithium hydroxide solution. The reaction medium is stirred at room temperature for 18 hours. 0.07 ml of aqueous 1M lithium hydroxide solution is added and the medium is heated for a further 5 hours. The reaction medium is diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. 55 mg (82%) of 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylureido)thiazol-5-yl]phenyl}propanoic acid are obtained in the form of a white solid with a melting point of 97° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.[C:13](=[N:18][OH:19])(Cl)[C:14]([CH3:16])=O.Cl>O1CCCC1>[N:18](=[C:13]1[C:14]([CH3:16])=[N:2][CH2:3][CH2:4][S:5]1)[OH:19]
Reactant: CC(=O)C(Cl)=NO
Reactant: NCCS
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=NCCSC1=NO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.27 g (0.02 mol) of cysteamine hydrochloride are suspended in 40 ml of absolute tetrahydrofuran and treated with 5.55 ml (0.04 mol) of triethylamine to free the base. The mixture is stirred for 15 minutes at room temperature and then cooled down to about -30° C. At this temperature a solution of 2.42 g (0.02 mol) of pyruvyl chloride 1-oxime in 10 ml of absolute tetrahydrofuran is added dropwise. The reaction mixture is allowed to warm to room temperature while being well stirred. After two hours ice-water and then dilute hydrochloric acid are added until a pH of 5-6 has been attained. The reaction mixture is extracted twice with ethyl acetate and the organic phase is washed with sodium chloride solution, dried over anhydrous sodium sulfate and finally evaporated. The resulting crystalline residue is treated with active charcoal. After recrystallization from hot ethyl acetate and n-hexane there is obtained pure 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime, m.p. 197° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:3]([N+:21]([O-:23])=[O:22])=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:24][SeH-:25](C)=[Se].[BH4-].[Na+].N1C=CN=CC(=O)C=1.C(CN)O>C(O)(C)C.O1CCOCC1>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[C:3]([N+:21]([O-:23])=[O:22])[C:2]([Se:25][CH3:24])=[N:12][C:11]1=2)[CH3:14]
Reactant: C[SeH-](C)=[Se]
Reactant: CCN1c2ncccc2C(=O)Nc2c1nc(Cl)c([N+](=O)[O-])c2C
Agent: O=c1cnccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: NCCO
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1c2ncccc2C(=O)Nc2c1nc([Se]C)c([N+](=O)[O-])c2C
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a mixture of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-3-nitro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.063 g) and dimethyldiselenide (0.11 g) in isopropanol (0.5 mL) in a pressure tube was added sodium borohydride (0.006 g). The tube was sealed and heated at 110° C. for 5 minutes and then left at room temperature for 3 days. The mixture was eluted from a short silica gel column (chloroform) and then fractionated by preparative layer chromatography to give a mixture of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-3-nitro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 5,11-dihydro-11-ethyl-4-methyl-2-methylseleno-3-nitro- 6H-dypyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one. The mixture was dissolved in dioxan (1 mL) and ethanolamine (0.1 g) was added. The mixture was heated at 100° C. for 2 hours whereupon the remaining starting material had reacted. Evaporation of the solvent and chromatography over silica gel gave the title compound which crystallized on trituration with diisopropyl ether, m.p. 261°-267° C. dec.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=2)[NH2:10])=[N:4][N:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:31][C:27]1[CH:26]=[C:25]2[C:30]([C:21]([NH:10][C:9]3[CH:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:13]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=3)=[C:22]([CH3:38])[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: Cc1nnc(-c2cc(N)cc(N3CCOCC3)c2)o1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2cc(Nc3c(C)c(-c4ccccn4)nc4cc(F)ccc34)cc(N3CCOCC3)c2)o1

Procedure:
Prepared according to Procedure N using 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-morpholinoaniline (0.034 g, 0.131 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.036 g, 0.131 mmol), sodium tert-butoxide (0.031 g, 0.327 mmol), XPhos precatalyst (CAS 1028206-56-5; 8.79 mg, 0.013 mmol), XPhos (6.23 mg, 0.013 mmol), and toluene (0.7 mL) to afford 7-fluoro-3-methyl-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(4-morpholinyl)phenyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (1H, s), 8.68-8.71 (1H, m), 8.07-8.15 (1H, m), 8.00 (1H, dd, J=7.6, 2.0 Hz), 7.88-7.91 (1H, m), 7.77 (1H, dd, J=10.3, 2.6 Hz), 7.48-7.54 (2H, m), 6.96 (1H, t, J=1.9 Hz), 6.72 (1H, t, J=1.7 Hz), 6.51 (1H, t, J=2.2 Hz), 3.70-3.74 (4H, m), 3.07-3.14 (4H, m), 2.52 (3H, s), 2.23 (3H, s). Mass Spectrum (ESI) m/e=497.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13](OCC)=[O:14].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:14][CH2:13][C:3]1[CH:4]=[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]2=[N:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(cc1CO)CCCCC2
Reaction time: 2 h
Yield: 72.8 %

Procedure:
In an atmosphere of argon, ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (586.6 mg, 2.51 mmol) was dissolved in anhydrous THF (5.0 ml), lithium aluminum hydride THF solution (1.0 M, 5.0 ml) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was mixed with sodium sulfate decahydrate at 0° C. and subjected to celite filtration. The resulting filtrate was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (349.5 mg, 72.8%) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[CH2:19][OH:20])=[C:14]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])[C:13](=[O:29])[CH:12]=[CH:11]2.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:32])=[O:20])=[C:14]([C:21]1[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=1[F:27])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: CC(C)=O
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)c(CO)ccc2c1-c1c(F)cccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(hydroxymethyl)-2H-quinolizin-2-one (Example 50, 100 mg) was added Jones reagent (0.5 mL, 4 N in sulfuric acid; prepared using procedure similar to that disclosed in Bowers, Halsall, Jones, and Lemin, J. Chem. Soc., (1953), 2548-2560) at 0° C. The mixture was stirred for a couple of hours at 0° C. until reaction complete and then quenched with isopropanol (1 mL). After stirring for 10 min (green solution), the mixture was filtered through celite and concentrated. The residue was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated to give title compound (87 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:27][CH2:28][CH2:29]Br>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Br:27][CH2:28][CH2:29][O:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:20])[CH3:19])=[CH:17][CH:16]=1
Reactant: CC(C)(COc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: CC(C)(COc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C

Procedure:
Analogously to Example (2b), a mixture of 19.2 g (68 mmol) of p-[2-(tertiary butoxycarbonylamino)-2-methylpropoxy]-phenol, 47 g (340 mmol) of potassium carbonate and 1.5 g of triethylbenzylammonium chloride is reacted in 57 ml (680 mmol) of 1,2-dibromoethane and worked up. Crude 1-(2-bromoethoxy)-4-[2-(tertiary butoxycarbonylamino)-2-methylpropoxy]-benzene is obtained in the form of an oil, which is used further in crude form.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:32][CH:33]1[CH:40]2[CH2:41][C:36]3([CH2:43][OH:44])[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][C:36]([CH2:43][OH:44])([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
3-Cyclohexylmethoxy-benzoic acid (300 mg, 1.3 mmol), HOBT (294 mg, 1.9 mmol), EDC (245 mg, 1.3 mmol), and 4-amino-1-hydroxymethyladamantane (232 mg, 1.28 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.6 mmol) was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was purified directly by Preparative HPLC to give 364 mg of the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.29-7.34 (m, 2H), 7.21-7.26 (m, 1H), 6.98-7.04 (m, 1H), 3.79 (dd, 2H), 6.43 (dd, 1H), 4.10-4.25 (m, 1H), 3.79 (dd, 2H), 3.23 (d, 2H), 2.43 (s, 1H), 2.10-2.16 (m, 2H), 1.97-2.04 (m, 1H), 1.55-1.92 (m, 14H), 1.39-1.47 (m, 1H), 1.15-1.35 (m, 13H), 1.05 (q, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[CH:11](O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Cc1cc(N)c(N)cc1Cl
Product: Cc1cc2[nH]cnc2cc1Cl
Temperature: 100 °C

Procedure:
4-Chloro-5-methyl-benzene-1,2-diamine (560 mg, 3.6 mmol, Maybridge Chemical Co. Ltd., Cornwall, UK) was dissolved in formic acid (10 mL) and the solution was refluxed at 100° C. for 18 hr. The reaction was allowed to cool and then evaporated to dryness in vacuo to give 5-chloro-6-methyl-1H-benzoimidazole as a tan solid (quantitative yield) that was used without further purification. The solid obtained above (410 mg, 2.4 mmol), di-tert-butyl dicarbonate (1.6 g, 7.4 mmol), and DMAP (29 mg, 0.24 mmol) were dissolved in CH3CN (20 mL). To the mixture, DIEA (1.3 mL, 7.4 mmol) was added and the reaction was stirred for 18 hr at rt. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (75 mL). The aqueous layer was separated and washed with EtOAc (100 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude residue was purified using flash SiO2 chromatography (20% EtOAc in hexanes) to give 620 mg (97%) of the title compound as a 1:1 mixture of regioisomers that were used without separation. 1H-NMR (CDCl3; 400 MHz, 1:1 mixture of isomers) δ 8.35 and 8.36 (s, 1H), 7.89 and 7.99 (s, 1H), 7.62 and 7.75 (s, 1H), 2.48 and 2.50 (s, 3H), 1.698 and 1.700 (s, 9H). ESI-MS (m/z): Calcd. for C13H15ClN2O2: 266.7; found: 266.9, 167.2 (M−Boc).
Reaction SMILES: CC(C)=O.[CH2:5]([O:7][C:8]([C:10]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15](Cl)=[C:16]([F:21])[CH:17]=2)[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=1)=[O:9])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([SH:35])[CH3:34]>O.C(OC(=O)C)C>[CH2:5]([O:7][C:8]([C:10]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([S:35][CH2:33][CH3:34])=[C:16]([F:21])[CH:17]=2)[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(SCC)c(F)cc2c1=O
Yield: 79 %

Procedure:
Acetone (90 mL) was added to a mixture of 1.96 g (6 mmoles) of 6-fluoro-7-chloro-1-(1,1-dimethylethyl)-1,4-dihydro-4-oxo-1,8 naphthyridine-3-carboxylic acid ethyl ester and 2.5 g (18 mmoles) of anhydrous potassium carbonate. To this suspension was added 1.33 mL (18 mmoles) of ethanethiol. After heating to reflux for 2.5 hours, the solvent was eliminated in vacuo. The residue was taken up with ethylacetate and water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The resulting solid was treated with ether to give 1.67 g of titled compound. MP 159°-60° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]3[C:9]([O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(CO)CO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)CO)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.546 g (14.85 mmol) 2,2-dimethylpropane-1,3-diol in 30 ml THF. Add 833 mg (7.42 mmol) potassium tert.-butylate and stir for a further 15 min at RT. Then cool to 0° C. and add a solution of 1.00 g (2.97 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 15 ml THF dropwise over a time of 30 min. Leave to return to RT and stir for a further 30 min at RT. Then add dichloromethane and water, acidify with 10% citric acid solution and separate the phases. Extract the aqueous phase once with dichloromethane. Combine the organic phases and wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. 1.20 g (99.9% of theor.) of the target compound is obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:32]=1>>[CH2:18]([S:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:35])=[O:36])[CH:32]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)(=[O:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(=O)(=O)c4ccccc4)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide (which was obtained in Example 21) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.55–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (t, J=7.6 Hz, 2 H), 3.50–3.90 (m, 5 H), 6.39 (d, J=8.7, 2.9 Hz, 1 H), 6.57 (d, J=8.7 Hz, 1 H), 6.72 (d, J=2.9 Hz, 1 H), 6.90 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2 H), 7.40–7.60 (m, 3 H), 7.74 (d, J=7.7 Hz, 2 H); MS (ES) m/z: 633.1 (MH+); HRMS Calcd. for C30H41N4O7S2 (MH+): 633.2411. Found: 633.2409.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[CH:32][N:33]2[CH3:38]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[CH:32][N:33]2[CH3:38]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: Cn1ccc2c(CN)cccc21
Product: Cn1ccc2c(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cccc21

Procedure:
Using a method similar to the General Procedure 5-1, couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetra-hydro-1H-benzo[d]azepine (0.1 g, 0.24 mmol) with 4-aminomethyl-1-methylindole (0.1 g, 0.71 mmol) to obtain 7-chloro-6-[(1-methyl-indol-4-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2.O>C1COCC1>[N:28]([C@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2c(c1)OCC[C@@H]2O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)OCC[C@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Azeotropically dried (S)-4-hydroxy-chroman-7-carbonitrile (2.0 g, 11 mmol) was dissolved in dry THF (55 ml). DPPA (3.0 ml, 3.8 g, 14 mmol) was added to the solution at RT and the mixture was stirred for 5 min. The solution was cooled to 0° C. and 1,8-diazabicyclo[5,4,0]undec-7-ene (2.0 mL, 2.1 g, 14 mmol) was added. After stirring for 10 min at 0° C., the reaction was warmed to RT, at which time a white precipitate formed, and was stirred for 14 h. The resulting solution was poured into H2O (100 mL) and extracted with Et2O (300 mL, 3×). The organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by flash column chromatography (silica, 33% hexane in CH2Cl2) to provide the title compound.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[N:49]=[C:48]([NH2:50])[CH:47]=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[N:49]=[C:48]([NH:50][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:47]=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (47 mg, 0.25 mmol) in CH2Cl2 (1.5 mL) was treated at rt with HOBt (40 mg, 0.30 mmol), EDC (119 mg, 0.62 mmol), DMAP (8 mg, 0.06 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (80 mg, 0.25 mmol) in CH2Cl2 (1.0 mL) was then added and the resulting mixture was stirred at rt for 72 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=1.17 min, [M+H]+=495.54.