Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:61][CH2:62][CH2:63][NH2:64])=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[CH2:61][CH2:62][CH2:63][NH:64][C:12]([C@@H:11]([NH:10][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:56][CH:55]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
(S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.644 mL, 3.70 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.367 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to afford 0.45 g (73%) of the pure titled compound as a white foam; mp 73-91° C. APCI-MS m/z 501.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](Cl)[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][N:17]1CCCC1=O.C([Cu])#N>O>[CH3:1][C:2]1[CH:10]=[C:9]([C:16]#[N:17])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Solvent: O
Product: Cc1cc(C#N)c(S(C)(=O)=O)cc1C(=O)O
Reaction time: 72 h

Procedure:
8.3 g of 2-methyl-4-chloro-5-methylsulphonylbenzoic acid are mixed together with 70 ml of N-methylpyrrolidone and 7.4 g of CuCN, and the whole is stirred at 150° for 3 days. The reaction mixture is then poured into 250 ml of water and working-up takes place in the customary manner. After recrystallization from methanol, 2-methyl-4-cyano-5-methylsulphonylbenzoic acid is obtained, m.p. 248°-249°.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.Br.[C:10]([O:18][CH:19]([CH3:33])[CH2:20][CH:21]1[CH2:26][O:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:24]([O:25][CH2:26][CH:21]([CH2:20][CH:19]([O:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:33])[CH2:22][OH:7])(=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(CC1COC(c2ccccc2)OC1)OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a stirred and ice cooled suspension of 9.344 g (52.5 mM) of N-bromosuccinimide in 250 ml of water are added a drop of conc. hydrobromic acid and 17.125 g of the crude 5-(2-benzoyloxypropan-1-yl)-2-phenyl-1,3-dioxane m4 obtained in the previous reaction dropwise. After standing at 0° C. for another 1 hour, 22 g (260 mM) of sodium bicarbonate is added to the reaction mixture and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (1:1) as an eluent gives 7.401 g (29.7% yield from the compound m2) of the titled compound m5 as an oily product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)C1CCN(C(=O)c2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (200 mg, 0.67 mmol), 2-piperidin-4-ylpropan-2-ol (105 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (130 μL, 0.75 mmol) in DCM (7 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) affording the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ 5.15 (1 H, d, J=13.36 Hz), 4.79 (1 H, d, J=13.25 Hz), 4.35 (4 H, brd s), 3.85 (4 H, t, J=4.75 Hz), 3.16-3.13 (1 H, m), 1.92 (2 H, t, J=15.39 Hz), 1.75-1.60 (1 H, m), 1.49-1.38 (4 H, m), 1.22 (6 H, d, J=6.97 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[C:11](O)(=O)[CH:12]([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[Cl-].[Ca+2].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(C)C(=O)O
Reactant: CNc1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2ccc(Br)cc2n1C

Procedure:
To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (122 mg) and isobutyric acid (0.056 ml) in DMF (2 ml) was added HATU (242 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. After being stirred, N,N-diisopropylethylamine (0.311 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was stirred in AcOH (2.00 ml) at 90° C. for 1 h and at room temperature overnight. The mixture was quenched with saturated NaHCO3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (119 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=2)[CH:7]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[Br:25][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12
Reactant: Fc1ccc(-c2cc3ccc(Cl)cn3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3cc(Cl)ccc3c2Br)cc1
Yield: 86.4 %

Procedure:
6-Chloro2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.48 g, 10.05 mmol) was dissolved in anhydrous DMF (160 ml) and treated with NBS (1.967 g) for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried and concentrated to give the title compound as a brown solid (2.827 g, 86%). (CDCl3) δ 7.19 (3H, t, J 9 Hz, H-3′+H-5); 7.48 (1H, d, J 9 Hz, H4); 8.05(2H, m, H-2′); 8.49 (1H, br s, H-7); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.74 detection uv254.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[O:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].[OH-].[Li+].O>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[O:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)#[N:2]
Reactant: COC(=O)CCc1nc(-c2cc(C#N)cc(C(F)(F)F)c2)co1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(-c2coc(CCC(=O)O)n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of methyl 3-(4-(3-cyano-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 46, 0.276 g, 0.851 mmol), lithium hydroxide (0.024 g, 1.00 mmol) and water (0.016 g, 0.889 mmol) was stirred at 0° C. for 4 h and then warmed to room temperature overnight. After this time, the reaction mixture was quenched with 1.0 M hydrochloric acid (1.0 mL), diluted with ethyl acetate and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by preparative HPLC (95% water-acetonitrile with 0.05% v/v trifluoroacetic acid/95% acetonitrile-water with 0.05% v/v trifluoroacetic acid 1:1, 15 mL/min) to provide 3-(4-(3-cyano-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.035 g, 13%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)C)[N:9]=[C:10](I)[C:3]=12.C([N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)[C:41]([CH3:57])=[N:40]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:9]=[C:10]([C:45]3[CH:46]=[C:47]4[C:42]([C:41]([CH3:57])=[N:40][NH:39]4)=[CH:43][CH:44]=3)[C:3]=12
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2cc(-c3nn(Cc4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
To a solution of Example 57c (0.477 g, 0.930 mmoles) in DMF (5.3 ml), ethanol (2.6 ml) and water (2.6 ml), N-Boc-3-methyl-6-indazoleboronic acid pinacol ester 98 (0.500 g, 1.395 mmoles) and sodium carbonate (0.295 g, 3.318 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.053 g, 0.046 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.100 g, 20% yield). MP: 246-248° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.22(s,1H), 8.06(dd, J=8.5,1.8Hz, 1H), 7.84(d, J=8.3Hz, 1H), 7.80(m,1H), 7.62(s,1H), 7.51(d, J=8.2Hz, 2H), 7.39-7.31(m, 2H), 7.18(m, 2H), 7.12(dt, J=8.3,2.6Hz, 1H), 5.56(s,2H), 2.51(s,3H). Mass: 517.51(M+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:25])[NH:12]2)[OH:6])=[N+]=[N-].[C:26]([OH:29])(=[O:28])[CH3:27]>[OH-].[Pd+2].[OH-].[C]>[C:26]([OH:29])(=[O:28])[CH3:27].[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:25])[NH:12]2)[OH:6]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 8 h

Procedure:
5-((R)-2-Azido-1-hyroxyethyl)-8-benzyloxy-1H-quinolin-2-one (16.8 g, 49.9 mol) was suspended in acetic acid (50 mL), a catalytic amount of palladium hydroxide-carbon was added thereto, and the solution was stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added methanol (100 mL) and ethyl acetate (100 mL), and the mixture was stirred. The precipitate was collected by filtration and dried to obtain 5-((R)-2-amino-1-hyroxyethyl)-8-hydroxy-1H-quinolin-2-one acetate (12.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]3([OH:31])[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>O1CCCC1.Cl>[OH:31][C:21]1([C:11]2[S:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[CH2:30][CH2:29][C:24](=[O:25])[CH2:23][CH2:22]1
Reactant: COc1ccc(-c2nc(C3(O)CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C3(O)CCC(=O)CC3)sc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
To a solution of 8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 96) (469 mg, 1.07 mmol) in tetrahydrofuran (5.4 mL), 6 M hydrochloric acid (5.4 mL) was added at 0° C., and the obtained solution was stirred at room temperature for 14 hours. The reaction solution was basified by pouring it into saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (352 mg, 0.895 mmol, 83%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:25][N:26]([CH:28]=O)[CH3:27]>C(Cl)Cl>[CH3:25][N:26]([CH:28]=[N:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:27]
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OCC
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OCC
Temperature: 55 °C

Procedure:
To a stirred solution of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 ml of DMF at 0° C. was added phosphorous oxychloride (2.24 ml, 24 mmol) during 15 m. The mixture was warmed to 55° C. and stirred for 45 m. The resulting solution was diluted with methylene chloride, cooled to 0° C., and treated with 80 ml of precooled N/1 sodium hydroxide during 5 m. The organic layer was separated and washed at 0° C. with with water. The solution was dried and concentrated to give an amber oil; NMR (CDCl3) δ 3.00(s, ME2N).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][C:25]=1[CH3:26].ClC1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(Cl)c1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester (example 24 c]) was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:4]3[CH2:7][C@@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 59.6 %

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (807 mg, 4.77 mmol) in chloroform (8 ml) were added triethylamine (0.67 ml, 4.77 mmol) and 4-methoxybenzenesulfonyl chloride (1.08 g, 5.25 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1S, 3R, 4R)-2-[(4-methoxyphenyl) sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.965 g, 60%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](I)[CH2:23][CH2:24][CH3:25]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:22][CH2:23][CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reactant: CCCCI
Product: CCCCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 2.2 g (0.012 mol) of n-butyliodide, the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising gum in a yield of 2.9 g (87.8% of theory) and with an Rf value of 0.69 (solvent mixture as specified in 4.7.1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.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]>[CH3:22][O:23][C:24](=[O:35])[C:25]([CH3:26])([N:28]1[CH2:29][CH2:30][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:21]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (300 mg, 0.877 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (286 mg, 1.315 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (51 mg, 10 mol %) and DIPEA (0.61 mL, 3.5 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The crude reaction mixture was diluted with DCM (150 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording 2-Methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propionic acid methyl ester as an orange oil (0.674 g, quantitative). LCMS: RT1.88 min [M+H]+ 479.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1)(355 mg, 1.0 mmol) and 3-Bromo-N-tert-butyl-benzenesulfonamide (example B.9) (321 mg, 1.1 mmol) according to general procedure II. Obtained as a light-brown solid (110 mg, 20%). MS (ISP) 567.2 [(M+H)+]; mp 192-200° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][S:8]([N:11]1[CH2:19][C:18]2[C:17]([C:20](OC)=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12]1)(=[O:10])=[O:9]>C1COCC1.[OH-].[Na+]>[CH3:7][S:8]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][OH:21])[CH2:12]1)(=[O:10])=[O:9]
Reactant: COC(=O)c1cccc2c1CN(S(C)(=O)=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1Cc2cccc(CO)c2C1
Yield: 61 %

Procedure:
Lithium aluminum hydride (LAH, 1 M in THF, 2 mL, 2.0 mmol) was added to solution of methyl 2-(methylsulfonyl)isoindoline-4-carboxylate in THF (15 mL). After 10 h the mixture was diluted with 5% NaOH solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. The residue was recrystallized from DCM to give the title compound (200 mg, 61%) as a grey solid.