Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:14][N:13]=[C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:57]([O:61][C:62](=[O:68])[NH:63][CH2:64][CH2:65][CH2:66][OH:67])([CH3:60])([CH3:59])[CH3:58].C(=O)([O-])N>C1COCC1>[C:22]([C:19]1[N:20]=[CH:21][C:16]([NH:15][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[O:67][CH2:66][CH2:65][CH2:64][NH:63][C:62](=[O:68])[O:61][C:57]([CH3:60])([CH3:58])[CH3:59])[NH:14][N:13]=2)=[N:17][CH:18]=1)#[N:23]
Reactant: COc1cccc(O)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Temperature: 0 °C
Reaction time: 0.06 h
Yield: 44.2 %

Procedure:
A 5 L flange-neck round-bottom flask equipped with an air stirrer rod and paddle, thermometer, pressure-equalizing dropping funnel, and nitrogen bubbler is charged with 5-(5-(2-hydroxy-6-methoxy-phenyl)-1H-pyrazol-3-ylamino)-pyrazine-2-carbonitrile (47.0 g, 152 mmol) and anhydrous THF (1.2 L). The stirred suspension, under nitrogen, is cooled to 0° C. A separate 2 L 3-necked round-bottom flask equipped with a large magnetic stirring bar, thermometer, and nitrogen bubbler is charged with triphenylphosphine (44.0 g; 168 mmol) and anhydrous THF (600 mL). The stirred solution, under nitrogen, is cooled to 0° C. and diisopropylazodicarboxylate (34.2 g; 169 mmol) is added and a milky solution is formed. After 3-4 min, a solution of t-butyl-N-(3-hydroxypropyl)-carbamate (30.3 g, 173 mmol) in anhydrous THF (100 mL) is added and the mixture is stirred for 3-4 min. This mixture is then added over 5 min to the stirred suspension of starting material at 0° C. The reaction mixture quickly becomes a dark solution and is allowed to slowly warm up to room temperature. After 6.5 h, more reagents are prepared as above using PPh3 (8 g), DIAD (6.2 g) and carbamate (5.4 g) in anhydrous THF (150 mL). The mixture is added to the reaction mixture, cooled to −5° C. and left to warm up to room temperature overnight. The solvent is removed in vacuo. The resulting viscous solution is loaded onto a pad of silica and product is eluted with ethyl acetate. The concentrated fractions are separately triturated with methanol and resulting solids are collected by filtration. The combined solids are triturated again with methanol (400 mL) and then isolated by filtration and dried in vacuo at 50° C. overnight to give 31.3 g of desired product. LC-ES/MS m/z 466.2 [M+1]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([O:22][CH3:23])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([O:22][CH3:23])[CH:14]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1cc(Br)oc1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(F)cc2OC)oc1C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 4-fluoro-2-methoxyphenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 51%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N+:11]([O-])[C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:20])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[OH-].[NH4+:22].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[C:10]([NH2:22])=[N:11][C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:20])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: [NH4+]
Reactant: CC1OC[C@H](C)n2c1nc1c[n+]([O-])c3ccccc3c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC1OC[C@H](C)n2c1nc1c(N)nc3ccccc3c12

Procedure:
A solution of (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (85 mg, 0.316 mmol) in 5 mL of CH2Cl2 was treated with 1 mL of concentrated aqueous ammonium hydroxide and stirred vigorously. p-Toluenesulfonyl chloride (60 mg, 0.316 mmol) was added in one portion. The following day the reaction was treated with 5 mL of H2O and 10 mL of CH2Cl2, and the layers were separated. The organic layer was washed sequentially with saturated NaHCO3 solution (2×) and brine, dried over Na2SO4, filtered, and concentrated to give a light yellow solid. Chromatography (AFC, SiO2, 0-20% CMA/CHCl3) afforded (11s)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (25 mg) as a white solid, m.p. 218-223° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[N+:43]([O-])=O)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:37])([CH3:36])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([F:33])[CH:25]=1)([CH3:18])[CH3:17].[H][H]>[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][Si:16]([CH3:17])([CH3:18])[O:15][Si:14]([CH3:35])([CH3:34])[O:13][Si:12]([CH3:37])([CH3:36])[O:11][Si:10]([CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:40]=[CH:41][C:42]([NH2:43])=[C:2]([F:1])[CH:3]=2)([CH3:38])[CH3:39])=[CH:25][C:26]=1[F:33]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])c(F)c1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)c(F)c1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)c(F)c1
Yield: 99.6 %

Procedure:
1.66 g of the above (2g) (2.35 mmol) and 10 mL of a 10 wt % Pd/C (0.0275 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis[4-(4-amino-3-fluorophenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3g) (1.51 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3 g), and results are shown below.
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)[Cl:3].[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Mg]Br>O1CCCC1>[CH3:6][CH:7]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][Si:2]([Cl:5])([Cl:3])[Cl:1]
Reactant: CC(C)CCCC(C)CC[Mg]Br
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrahydrofuran (100 ml) and tetrachlorosilane (17.0 g, 100 mmol) were placed in a 500 mL four-necked flask in a nitrogen atmosphere, and cooled to −10° C. 3.7-dimethyloctyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 100 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target 3,7-dimethyloctyl trichlorosilane (99-102° C./0.3 Torr, 22.3 g, yield 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.CCCCCC.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 1,3-bis{[(methyloxy)methyl]oxy}benzene (Reference Intermediate 208, 2.19 g) in dry tetrahydrofuran (10 ml) at room temperature BuLi 1.6M in hexane (8.29 ml, 13.26 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (2.263 g, 16.57 mmol) in dry tetrahydrofuran (10 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml) and extracted with ethyl acetate (2×30 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound as a light yellow oil (1.75 g).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:26]5[S:27][CH:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:25]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1nc(C(F)(F)F)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (49 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (68.3 mg) and triphenylphosphine (137 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (122 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (21.5 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.Br[CH2:14][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C>CCOCC>[OH:16][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH2:8][CH2:9]1
Reactant: NC(=O)c1cc(C(O)CBr)ccc1O
Reactant: Cc1csc(N2CCNCC2)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1csc(N2CCN(CC(O)c3ccc(O)c(C(N)=O)c3)CC2)n1
Reaction time: 2 h

Procedure:
18.9 g of 1-(4-methyl-2-thiazolyl)-piperazine and 26 g of 5-(2-bromo-1-hydroxyethyl)-salicylamide (obtainable by acylation of salicyamide with bromoacetyl bromide/AlCl3 to give 5-bromoacetyl-salicylamide and subsequent reaction with NaBH4) are dissolved in 400 ml of ether, 15 ml of triethylamine are added, the mixture is boiled for 2 h and subjected to the usual working-up, and 5-[1-hydroxy-2-(4-(4-methyl-2-thiazolyl)-piperazino)-ethyl]salicylamide ("A"), m.p. 182°, is obtained. Dihydrochloride m.p. 244°-245°.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.[CH3:22]CN(CC)CC.[N:29]12[C:35](=[O:36])[CH2:34][CH:33]1[CH2:32][C:31](=O)[CH:30]2[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl.ClCl>[C:19]1([CH3:22])[C:14]([S:11]([O:10][C:31]2[CH2:32][CH:33]3[N:29]([C:35](=[O:36])[CH2:34]3)[C:30]=2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(=[O:12])=[O:13])=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: ClCl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic anhydride (33 mg, 0.1 mmol) and Et3N (17 μl, 0.12 mmol) are added to a solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (26 mg., 0.1 mmol) in anhydrous CH2Cl2 (2 ml). The resulting solution is stirred at room temperature for 2 hours. The mixture is diluted with CH2 Cl2 (10 ml), washed with H2O (2×5 ml), pH 3 phosphate buffer (5 ml) and 5% NaHCO3 (5 ml), dried with MgSO4, filtered and evaporated i.v. to provide benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:19][C:20](=[O:36])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]=[CH2:35])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:36])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]2[CH2:35][O:6]2)=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NCCCCc1ccc(OCC2CO2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
3-Chloro-peroxybenzoic acid (2.46 g, 14.25 mmol) was added into a methylene chloride solution (100 mL) of 38 (1.86 g, 5.48 mmol), and the reaction was stirred at room temperature overnight. After that, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 8:1:1 methylene chloride/hexane/ethyl acetate). To eliminate the admixture of benzoic acid the methylene chloride solution of the product was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous sodium sulfate and evaporated to provide 1.4 g (72%) of 39 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.57 (m, 4H), 2.56 (m, 2H), 2.78 (m, 1H), 2.91 (m, 1H), 3.21 (m, 2H), 3.36 (m, 1H), 3.97 (m, 1H), 4.19 (m, 1H), 5.08 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.72 (s, 5H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
Lithium hydroxide monohydrate (0.019 g, 0.46 mmol) was added to a stirred solution of {6-chloro-4-[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.057 g, 0.114 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.043 g, 77%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H) 8.23 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.86-7.93 (m, 3 H) 7.70-7.78 (m, 1 H) 7.56 (d, J=8.80 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.96 (s, 1 H) 3.85 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C25H16ClF2O4S [(M−H)−] 485, obsd. 485.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=3)=[S:29])=[CH:7][CH:6]=1)[CH:18]=[CH:17]2
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4cc(Cl)ccc4n3)cc2)ccc1Cl
Yield: 51.3 %

Procedure:
2-(4-Aminophenylthio)-6-chloroquinoline (2.9 mmoles, 0.83 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.2 mmoles, 0.76 g) were reacted according to procedure C to yield 0.78 g, 51% of the title compound. Mass Spec (FD) 524. Calculated for C23H14ClF3N3S2 : C, 52.68; H, 2.69; N, 8.01. Found: C, 52.66; H, 2.78; N, 7.91. M Pt 138°-139° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=3)[CH2:22][C:21](=[O:33])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCCC4)c(F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-fluoro-5-pyrrolidin-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M47) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (54 mg).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (2S,5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 19, 80 mg, 0.136 mmol) in dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (88 mg) that was used in the next step without further purifications.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][CH3:36].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (24.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.20 g). To the solution was added 60% sodium hydride (0.24 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1-bromo-2-butyne (0.80 ml), and the mixture was stirred at 65° C. for 4 days. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g).