Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a slurry of 4-hydroxythiophenol (259.4 g, 2.06 mol) and potassium carbonate (284.2 g, 2.06 mol) in 500 mL of DMF at 0° C. was added tert-butyl 3-chloropivaloate (373.8 g, 1.94 mol) dropwise over 2 hours. After stirring to room temperature overnight, the reaction was heated to 110° C. for 3 hours. The reaction was allowed to cool for room temperature and water and ether were added. The layers were separated and the organic layer washed with water and 5% NaOH, dried over MgSO4 and concentrated. The resulting oil was recrystallized from 1:3 CH2Cl2 /pet. ether to afford 328.0 g (60%) of the desired product. mp 100°-100.5° C.; 1H NMR (CDCl3) δ1.22 (s,6H), 1.44 (s,9H), 3.07 (s,2H), 5.42 (br s,1H,--OH), 6.77 (d,2H,J=8.7 Hz); 13C NMR (CDCl3) δ 24.62, 27.73, 44.58, 46.86, 81.00, 116.2, 127.7, 133.5, 155.4, 176.7; IR (KBr, film) 3362, 2971, 1720, 1693, 1600, 1583, 1495, 1472, 1366, 1320, 1223, 1150(s), 835, 817 cm-1.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].NCCCC[C:10]1[C:11](=[N:29][C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=2[CH3:38])[NH:12][C:13](=[O:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=3)[C:15]=12>O.Cl>[C:2]([NH:12][CH2:11][CH2:10][CH2:15][CH2:16][N:12]1[C:11](=[N:29][C:30]2[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])[CH:10]=[C:15]2[C:16]3[C:21]([CH2:22][CH2:23][N:14]2[C:13]1=[O:28])=[CH:20][C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)(=[O:1])[NH2:3]
Reactant: COc1cc2c(cc1OC)-c1c(CCCCN)c(=Nc3c(C)cc(C)cc3C)[nH]c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCCCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Yield: 128.2 %

Procedure:
Sodium cyanate (0.28 g, 4.32 mmol) in water (6 ml) was added dropwise to a stirred solution of 2 (1.0 g, 2.16 mmol) in water (30 ml) and 1N HCl (4.3 ml) at 80° C. After 2 h at 80° C. the mixture was cooled and extracted with dichloromethane (3×20 ml) and the extract dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel [dichloromethane/methanol (97:3)] to obtain the title compound (0.70 g, 64%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=S)[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1.[NH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[N:16]=[C:15]([NH2:22])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1
Reactant: N
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=S)N1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 60 °C
Reaction time: 40 h
Yield: 55.6 %

Procedure:
A mixture of (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-thione (1.05 g, 2.68 mmol, Eq: 1.00) and ammonia (7 N in MeOH) (19.1 ml, 134 mmol, Eq: 50) was stirred in a sealed tube for 40 hours at 60° C. Extracted with ethyl acetate and sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed on 20 g silica gel with ethyl acetate to give (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (560 mg, 1.49 mmol, 55.8% yield) as a white solid. MS (ISP): m/z=375.0 [M+H]+ and 377.4 [M+2+H]+.
Reaction SMILES: [O:1]1[C:16]([CH3:18])([CH3:17])[CH:2]1[CH2:3][CH2:4]/[C:5](/[CH3:15])=[CH:6]/[CH2:7][CH2:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([NH2:13])=[O:12].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].Cl>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4]/[C:5](/[CH3:15])=[CH:6]/[CH2:7][CH2:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([NH2:13])=[O:12]
Reactant: C/C(=C\C(N)=O)CC/C=C(\C)CCC1OC1(C)C
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C/C(N)=O

Procedure:
A solution of 4.8 g of (E,E)-10,11-epoxy-3,7,11-trimethyl-2,6-dodecadienamide in 70 ml of toluene is treated with 4.48 g of aluminum isopropylate, whereupon the mixture is boiled under reflux for 4.5 hours. The cooled reaction mixture is poured into a mixture of 2N hydrochloric acid and ice, whereupon the mixture is extracted with 2×100 ml of ether. The combined organic extracts are washed with water and with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on 230 g of aluminum oxide (basic, activity III), elution being carried out with hexane-ethyl acetate (20% to 100%) and then with ethyl acetate-methanol (10%). There is obtained (E,E)-10-hydroxy-3,7,11-trimethyl-2,6,11-dodecatrienamide as a yellowish, viscous oil. IR (film): 3335, 3195 (OH and NH2); 1668 (amide C=O). MS (CI with NH3): 252 (M+H)+ ; 251 (M+NH4 -H2O)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[N:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)nn1-c1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a mixture of 4-t-butylbenzenesulfonyl chloride (0.067 g, 0.29 mmol) and 1-(quinolin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.011 g, 0.04 mmol) in pyridine (0.5 mL) was heated at 80° C. for 2 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol), and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.006 g, 0.013 mmol, 32%). 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J=1.6, 4.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.48 (s, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.27-7.24 (m, 1H), 7.09 (d, J=6.0 Hz, 1H), 6.70 (s, 1H), 1.38 (s, 9H); MS: (ES) m/z calculated for C23H22F3N4O2S [M+H]+ 475.2. found 475.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:25][CH:26]([CH3:30])[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH:26]([CH3:30])[CH3:25])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reaction time: 8 h

Procedure:
4-(2-Chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine from Example 148 (40 mg) was added to a pre-stirred (15 minutes) solution of 2-methylpropanoic acid (2 eq.), 1-Hydroxybenzotriazole (1.2), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 eq.), diisopropylethylamine (DIPEA, 5 eq.) in N,N-Dimethylformamide (0.9 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of 1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)-2-methylpropan-1-one.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.4 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as a white solid (0.064 g, 13%). MS (ISP) 512.3 [(M+H)+]; mp 240.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: c1ccc2nc(CC3CCCCN3)ccc2c1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2ccc3ccccc3n2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 1, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.09 g, 0.35 mmol) and 2-piperidin-2-ylmethyl-quinoline, D13 (0.053 g, 0.23 mmol) as a colourless solid (0.038 g, 37%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[O:9][C:10]([C:18]3[CH:29]=[CH:28][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12.[S:30]1[CH2:34][CH2:33][S:32][CH:31]1[CH2:35][NH2:36].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][O:22][C:21]1[CH:28]=[CH:29][C:18]([C:10]2[O:9][C:4]3=[N:5][CH:6]=[C:7]([F:8])[C:2]([NH:36][CH2:35][CH:31]4[S:32][CH2:33][CH2:34][S:30]4)=[C:3]3[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:19][CH:20]=1
Reactant: CN(C)CCOc1ccc(-c2oc3ncc(F)c(Cl)c3c2-c2ccccc2)cc1
Reactant: NCC1SCCS1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOc1ccc(-c2oc3ncc(F)c(NCC4SCCS4)c3c2-c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
The mixture of (2-[4-(4-chloro-5-fluoro-3-phenyl-furo[2,3-b]pyridin-2-yl)-phenoxy]-ethyl)-dimehtylamine (7) (30.0 mg, 0.07 mmol), 1,3-dithiolan-2-methylamine (65.8 mg, 0.49 mmol) and diisopropylethylamine (63.0 mg, 0.49 mmol) in NMP (0.6 mL) was heated to 150° C. with stirring under N2 overnight. The reaction mixture was purified by silica gel column chromatography, eluting with DCM/MeOH, 9/1, to give the title compound. MS (m/z), M+H+ 510.0.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12]C)=O)=[O:7])(C)(C)C.Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CCCCCCC.CCOC(C)=O>[Si:27]([O:12][CH2:10][C@H:9]1[C@H:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:19][CH:20]=2)[O:7][C:6](=[O:5])[NH:8]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 12 starting with (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate and (3-bromopropoxy)(tert-butyl)dimethylsilane. TLC (heptane/EtOAc 1:1) Rf=0.49; tR=1.832 min (UPLC 1); LC-MS: [M+H] 496; Rt 1.62 min (LC-MS method 1); 1H NMR (400 MHz, CDCl3): 7.30 (d, 2H), 6.95 (d, 2H), 5.27 (br s, 1H), 5.22 (d, 1H), 4.13 (dd, 2H), 4.00 (m, 2H), 3.80 (m, 3H), 3.74 (m, 2H), 2.01 (m, 2H), 0.93 (s, 9H), 0.91 (s, 9H), 0.10 (s, 6H), 0.06 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:20]4[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3cccnc3F)cccc21
Product: CC1c2cccc(-c3cccnc3F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.[O:2]=[C:3]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: Cl
Product: O=C(CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1cccs1
Yield: 32.3 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxo-4-(thien-2-yl)butanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 91, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-(thien-2-yl)butanoyl)pyrrolidine-2-carboxamide (10.8 mg, 32.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.84 (s, 1H), 7.95 (m, 2H), 7.53 (m, 2H), 7.29 (m, 2H), 7.24-7.14 (m, 8H), 6.91 (m, 2H), 4.43 (t, 1H), 3.69 (m, 1H), 3.24 (m, 1H), 3.05 (m, 2H), 2.67-2.59 (m, 5H), 1.91 (m, 2H). MS (EI) for C32H29FN2O4S. found 557.7 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:30]1[C:34]2([CH2:39][CH2:38][NH+:37]([CH2:40][B-](F)(F)F)[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:40][N:37]5[CH2:36][CH2:35][C:34]6([O:30][CH2:31][CH2:32][CH2:33]6)[CH2:39][CH2:38]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)C[NH+]1CCC2(CCCO2)CC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCC4(CCCO4)CC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (1-oxa-8-azonia-spiro[4.5]dec-8-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.93 min; Mass spectrum (ESI+): m/z=546 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[N:3]1.[CH3:14][Mg]Br.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[OH:13][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1cnn(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1cnn(C)c1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 500 mg of ethyl (1-methyl-1H-pyrazol-4-yl)(oxo)acetate that had been cooled in a dry ice-acetone bath in 7.5 ml of THF was added 1.56 ml of a 3.0 M methyl magnesium bromide/diethyl ether solution, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 302 mg of ethyl 2-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)propanoate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([C:15]([NH:18]S(C(C)(C)C)=O)([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[ClH:25].[NH2:18][C:15]([C:12]1[N:13]=[N:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[N:8][CH:7]=2)=[CH:10][CH:11]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc(-c2ccc(CO)nc2)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(N)c1ccc(-c2ccc(CO)nc2)nn1
Reaction time: 0.75 h

Procedure:
2-Methyl-propane-2-sulfinic acid{1-[6-(6-hydroxymethyl-pyridin-3-yl)-pyridazin-3-yl]-1-methyl-ethyl}-amide (4 mg, 0.011 mmol) was dissolved in CH2Cl2 (0.25 mL) and 4M HCl in dioxane (2 mL, 8 mmol) was added. After 45 minutes, the solvent was removed under a stream of N2 to give {5-[6-(1-amino-1-methyl-ethyl)-pyridazin-3-yl]-pyridin-2-yl}-methanol dihydrochloride as a crude light brown solid residue. This was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:12]=[O:13])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([CH:12]([OH:13])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:22])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(=O)Nc1cccc(F)c1C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Nc1cccc(F)c1C(O)c1ccccc1C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
100 mg (0.83 mmol) N-(3-fluoro-2-formyl-phenyl)-acetamide are dissolved in 4 ml of tetrahydrofuran and cooled to −78° C. Then at this temperature 1.66 ml (3.3 mmol) of a 2 M solution of o-tolylmagnesium bromide in diethyl ether are added. This reaction mixture is thawed to ambient temperature overnight with stirring. Then the reaction mixture is stirred into 30 ml dist. water and extracted three times with 10 ml of ethyl acetate. The organic phase is dried with MgSO4, the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28]N(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].IC>CC1C=CC=CC=1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)([C:14]([O:16][CH3:28])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: Cc1ccccc1
Product: COC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 78 parts of 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino]-4-piperidinecarboxylic acid in 470 parts of dry hexamethylphosphoric triamide are added portionwise 6.3 parts of sodium hydride dispersion 78% (slightly exothermic reaction). After stirring for one hour at room temperature, 29.3 parts of iodomethane are added dropwise. Upon completion, stirring is continued overnight at room temperature. Methylbenzene is added and the whole is washed with water. The organic phase is separated, washed with a sodium hydroxide solution 10% and with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 1,1'-oxybisethane and 2-propanol. After stirring vigorously, the salt is filtered off and crystallized twice from 4-methyl-2-pentanone, yielding methyl 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino]-4-piperidinecarboxylate; mp. 120.4° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[C:39]([O-:42])(=[O:41])[CH3:40].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:39]([O:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)(=[O:41])[CH3:40]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
10.0 g of 4-(bromomethyl)-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl and 3.5 g of cesium acetate are suspended in 300 ml of anhydrous DMF and stirred at 45° C. for 24 h. The solvent is evaporated off under reduced pressure and the residue is taken up in water, to obtain a solid which can easily be filtered. After drying, the solid is triturated with an hexane: ethyl acetate mixture (4:1) to obtain 7.2 g of a beige powder (Yield: 75%).