Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[S:34].C(=O)C1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[C:38]3[S:32][C:33](=[S:34])[NH:35][C:36]3=[O:37])=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=O)cc2)c(CCC)c1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=C3SC(=S)NC3=O)cc2)c(CCC)c1O
Yield: 84 %

Procedure:
The 4-[(4-decanoyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde thus obtained was coupled with the rhodanine by reacting equimolar amounts of the benzaldehyde and the rhodanine in the presence of sodium acetate and acetic acid as previously described to yield 1.6 g (84%) of the title product. mp 187.5-188° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-(1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyridazine (20 mg, 0.047 mmol) in 8 mL EtOH is added 10% Pd—C (25 mg, 19 mmol). The reaction mixture is stirred under hydrogen atmosphere for 16 h. The mixture is filtered throug Celite and the filtrate is concentrated to afford a off-white solid. The mixture is purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (8 mg, 40%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([OH:3])=O.[C:12](C1NC=CN=1)([C:14]1[NH:15][CH:16]=[CH:17]N=1)=O.C(NCC)C.O>O1CCCC1>[CH2:14]([N:15]([CH2:16][CH3:17])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=1)[CH3:12]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(C=O)c1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 3-carboxybenzaldehyde (5.0 g, 33.3 mmol) in 50 mL of tetrahydrofuran was added carbonyl diimidazole (5.67 g, 35.0 mmol) under Argon. After 1 h of stirring, diethylamine (4.87 g, 66.7 mmol) was added, and the reaction mixture was stirred for 18 h and then refluxed one hour. After cooling, water (50 mL) was added to the reaction flask, and the contents were concentrated on a rotary evaporator. The resulting mixture was extracted three times with dichloromethane (50 mL). These extracts were combined, washed twice with 1 N aqueous hydrochloric acid solution (50 mL) and twice with water (50 mL), dried (Na2SO4), and concentrated to give a yellow oil. This material was purified on flash silica gel (1% methanol-chloroform to 3% methanol-chloroform) to provide 4.68 g (68% yield) of N,N-diethyl(3-formyl)benzamide as a light green oil. MS (ES), m/z 206 (MH+). 300 MHz 1H NMR (CDCl3) δ1.13 (br s, 3H), 1.27 (br s, 3H), 3.26 (br d, J=5.5 Hz, 2H), 3.58 (br d, J=5.5 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.87-7.96 (m, 2H), 10.04 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22]Cl.O>CN(C=O)C>[CH3:20][O:21][CH2:22][O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7]
Reactant: COCCl
Reactant: N#Cc1ccnc(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(hydroxymethyl)isonicotinonitrile (5.08 g) and N-ethyldiisopropylamine (26.5 mL) in DMF (76 mL) was added chloromethyl methyl ether (8.63 mL) at room temperature, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.87 g) as an orange oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:12])[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=1.[C:13]1([CH2:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C.[Cu+2].[I-].[I-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:4]1[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=[C:2]([C:22]#[C:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#CCCc1ccccc1
Reactant: CCOC(=O)n1cc(I)nc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [I-]
Solvent: CCN(CC)CC
Product: CCOC(=O)n1cc(C#CCCc2ccccc2)nc1C
Temperature: 25 °C
Yield: 70.2 %

Procedure:
In a dry reaction tube containing in suspension iodide copper (20 mg, 0.1 mmol) and triethylamine (5.81 mL 41.40 mmol), were added ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (580 mg, 2.07 mmol) and the Pd(PPh3)2Cl2 (66 mg, 0.1 mmol). A yellow suspension is obtained and after a few minutes stirred at room temperature was added the commercially available 4-phenyl-1-butyn (269 mg, 2.07 mmol) in triethylamine (0.5 mL). Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine, dried (MgSO4) and concentrated. Purification by flash chromatography (prepacked 25 g silicagel column, DCM/MeOH: 99/1 as eluent to afford 410 mg of ethyl 2-methyl-4-(4-phenylbut-1-ynyl)-1H-imidazole-1-carboxylate (Yield: 70%) as a brown oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[N-:11]=[C:12]=[O:13]>>[CH3:3][CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:13]
Reactant: [N-]=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: CC(C)CCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6f was synthesized from benzo[d]isothiazol-3-one and isocyanate 4a′ as a white solid. mp 49-51° C.; IR(CHCl3) 3289, 1711, 1662, 1538 cm−1; 1H-NMR (DMSO-d6) δ0.84 (d, J=6.6 Hz, 6H), 1.13-1.20 (m, 2H), 1.26-1.32 (m, 2H), 1.47-1.55 (m, 3H), 3.28-3.34 (m, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 8.84 (br t, J=5.5 Hz, 1H); ESIMS m/e 293 (M++1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>ClCCl>[CH2:30]([O:29][CH2:28][O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.12 g, 8.65 mmol) and N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) in dichloromethane (30 mL) was added benzyl chloromethyl ether (2.71 g, 17.3 mmol). After stirring at room temperature for 18 h, the mixture was poured into water. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3) to give 2.29 g (72%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(Cl)=CCCCCCCl
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCCCSCc1ccccc1
Yield: 63.3 %

Procedure:
Operating as described in Example 10, from 3 g of 1,7-dichloro-1-fluoro-hept-1-ene, 2.14 g of benzylmercaptan, 0.7 g of NaH (at 55% concentration in paraffin oil) and 30 ml of N,N-dimethylformamide there were obtained 2.8 g of product which was purified in a chromatography column.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:16]([C:18]1[C:19]([CH3:27])=[C:20]([CH2:25][OH:26])[C:21]([CH3:24])=[CH:22][CH:23]=1)#[N:17].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:26][CH2:25][C:20]2[C:21]([CH3:24])=[CH:22][CH:23]=[C:18]([C:16]#[N:17])[C:19]=2[CH3:27])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Cc1ccc(C#N)c(C)c1CO
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Yield: 16 %

Procedure:
Cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (4.28 g, 0.018 mole) was added dropwise to a cooled solution of (3-cyano-2,6-dimethylphenyl)-methanol (2.93 grams, 0.018 mole) and pyridine (1.5 grams, 0.02 mole) in toluene (100 ml), and the mixture was allowed to come to room temperature. The solution was poured over crushed ice and extracted with methylene chloride. The combined organic extracts were washed successively with water, 5% aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate solution. The organic phase was dried with magnesium sulfate, filtered and the solvent evaporated. The residue was chromatographed on a silica gel column, elution with heptane, then heptane/methylene chloride to give (3-cyano-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (1.11 grams, mp 98°).
Reaction SMILES: C[Mg]I.[CH2:4](OCC)C.[CH2:9]([C:11]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:14]2([CH3:15])[C:13](=[O:31])[CH:12]=1)[C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:19][CH2:18]3)[CH3:10].[Cl-].[NH4+].N>O1CCCC1.[Cu]I>[CH2:9]([C@:11]1([CH3:4])[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:14]2([CH3:15])[C:13](=[O:31])[CH2:12]1)[C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:19][CH2:18]3)[CH3:10]
Reactant: CCOCC
Reactant: CCC1=CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: [Cu]I
Agent: C[Mg]I
Agent: N
Solvent: C1CCOC1
Product: CC[C@@]1(C)CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A solution of methylmagnesium iodide (2.5 mmol) in dry diethyl ether (2.5 ml) [prepared at 20° C. from magnesium (60 mg; 2.5 mmol) and methyl iodide (0.16 ml; 2.5 mmol)] was cooled to 0° C. Copper(I) iodide (46 mg; 0.24 mmol) was added. After 5 min. at 0° C., a solution of the 15-ethyl-Δ15 -17-ketone (7) (150 mg; 0.48 mmol) in dry tetrahydrofuran (3 ml) was added. The mixture was stirred at 20° C. for 15 min. Saturated aqueous ammonium chloride and aqueous ammonia were added and the residue upon work-up (ethyl acetate) (150 mg; 96%) was crystallized from chloroform to give the 15α-ethyl-3-methoxy-15β-methylestra-1,3,5 (10)-trien-17-one (8) (127 mg; 81%); m.p. 110°-113° C. (from chloroform-methanol); [α]D +90° (c 1.0); νmax 1724 cm-1 (CO); δH 0.89 (3H, t, J 7.4 Hz, 15α-CH2CH3), 1.12 (3H, s, 13β-Me), 1.25 (3H, s, 15β-Me), 1.36 and 1.76 (each 2H, degen. dq, J 14.8 and 3×7.4 Hz, 15α-CH2CH3), 2.18 and 2.44 (each 1H, d, J 19.4 Hz, 16α- and 16β-H), 2.88 (2H, m, 6-H2), 3.77 (3H, s, 3-OMe), 6.62 (1H, d, J 2.9 Hz, 4-H), 6.71 (1H, dd, J 8.6 and 2.9 Hz, 2-H), and 7.20 (1H, d, J 8.6 Hz, 1-H); δc 9.4 (C-152), 18.2 (C-18), 21.8 (C-151), 26.1 (C-11), 28.3 (C-7), 29.9 (C-6), 34.2 (C-12), 37.5 (C-8), 38.1 (15β-Me), 38.9 (C-15), 44.9 (C-9), 49.8 (C-16), 50.0 (C-13), 55.2 (3-OMe), 56.6 (C-14), 111.6 (C-2), 113.6 (C-4), 126.5 (C-1), 132.2 (C-10), 137.4 (C-5), 157.6 (C-3), and 220.4 (C-17) (Found: C, 81.2; H, 9.5%; M+, 326. C22H30O2 requires C, 80.9; H, 9.3%; M, 326).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A cooled (0° C.) solution of (4-bromo-3-fluorophenyl)methanol (Intermediate 9; 299 mg; 1.46 mmol) and methanesulfonyl chloride (147 μL; 1.90 mmol) in DCM (3 mL) was treated slowly with a solution of triethylamine (305 μL; 2.19 mmol) in DCM (1.5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes before being quenched by addition of water. The organic phase was washed with HCl (0.1N in water) and brine, dried over MgSO4, filtered and concentrated to dryness affording a residue, which was purified by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colourless liquid.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:19])=O>O1CCCC1>[ClH:19].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:1])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc(CN2CCCC2)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride (850 mg, 3.5 mmol) in dry tetrahydrofuran was treated with 2.55 mL of thionyl chloride (35 mmol, 10 eq) and stirred at room temperature for 2 hours. The solution thus obtained was then evaporated to dryness, the residue suspended in dry toluene, evaporated to dryness and dried under vacuum affording the title compound as pale brown solid (quantitative).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:18])[C:15]([O:29]C)=[N:14][C:13]([CH3:31])=[C:12]2[C:32](=[O:34])[CH3:33])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:18])[C:15](=[O:29])[NH:14][C:13]([CH3:31])=[C:12]2[C:32](=[O:34])[CH3:33])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous 6 N aqueous HCl (4 mL) was added to a stirring solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5° C., and the mixture was allowed to warm to room temperature. After 2 h, the solvent was evaporated and the product was dried under vacuum, giving the desired product as a pure single component which was used in the next step without further purification (3.88 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9](Br)[C:8](=[O:12])[N:7]2[C:13]([CH3:27])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)[N:15]=[C:6]12.O=O.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8](=[O:12])[N:7]2[C:13]([CH3:27])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)[N:15]=[C:6]12
Reactant: Cc1c(-c2ccc(OCC3CC3)cc2)nc2n(Cc3c(F)cccc3F)cc(Br)c(=O)n12
Reactant: OB(O)c1ccccc1
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: O=O
Solvent: COCCOC
Product: Cc1c(-c2ccc(OCC3CC3)cc2)nc2n(Cc3c(F)cccc3F)cc(-c3ccccc3)c(=O)n12
Yield: 80.4 %

Procedure:
The compound obtained in Example 24 (0.02 g, 0.04 mmol) is added to DME (30 ml), which is oxygen free. To this mixture is added phenylboronic acid (0.0054 g, 0.044 mmol), 2N aqueous K2CO3 solution (0.1 ml), tetrakis(triphenylphosphine)palladium(0) (0.0046 g, 0.004 mmol). Then the mixture is refluxed for 3 hours under argon atmosphere. The residual reaction mixture is partitioned between ethyl acetate (100 ml) and water (30 ml). The aqueous layer is extracted with ethyl acetate (30 ml). The combined organic extract is dried over Na2SO4 and concentrated under reduced pressure to give the residue, which is chromatographed on silica gel to afford white crystals (0.016 g, 78%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:23][C:24]1[CH:31]=[C:30]([O:20][C@H:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=3)[N:14]=2)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=Cc1ccc(O)cc1Cl
Product: CCCC[C@H](Oc1ccc(C=O)c(Cl)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 35 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 starting from (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (202 mg, 0.65 mmol) and 2-chloro-4-hydroxybenzaldehyde (140, 0.89 mmol) to afford the title compound (102 mg).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[O:28][CH3:29])[CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:34])[N:12]3[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.[CH2:37]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:37])[CH2:24][CH:23]4[O:28][CH3:29])[CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:34])[N:12]3[C:30]([O:32][CH3:33])=[O:31])=[CH:35][CH:36]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4OC)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reactant: C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4OC)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C

Procedure:
(2S)-Methyl 5-(4-fluorophenoxy)-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (2S)-methyl 5-(4-fluorophenoxy)-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and formaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (d, J=6.80 Hz, 3H), 1.50-1.65 (m, 1H), 1.98-2.11 (m, 1H), 2.15-2.22 (m, 1H), 2.40-2.70 (m, 3H), 2.78-3.01 (m, 5H), 3.02-3.18 (m, 1H), 3.42-3.85 (m, 8H), 4.15-4.25 (m, 1H), 4.55-4.72 (m, 1H), 6.72-6.80 (m, 2H), 6.90-7.01 (m, 2H), 7.50-7.62 (m, 2H), 7.80-8.10 (m, 2H). MS (ESI, pos. ion) m/z 509 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]I>CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:7]([N:5]1[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]1)[C:8]([OH:10])=[O:9]
Reactant: ClCCCCI
Reactant: O=C(O)Cn1cc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCCl)n1cc(Cl)cn1
Yield: 56.3 %

Procedure:
Step AK (1): 2-(4-Chloro-1H-pyrazol-1-yl)acetic acid (2.5 g, 15.57 mmol) was deprotonated with NaHMDS (1.0 M in THF, 31.0 mL, 31.0 mmol) and reacted with 1-chloro-4-iodobutane (1.91 mL, 15.6 mmol) using a procedure analogous to Step AC (1) to afford, after silica gel column chromatography (10-75% EtOAc/heanes), 6-chloro-2-(4-chloro-1H-pyrazol-1-yl)hexanoic acid (2.2 g, 56% yield). LC-MS (M−H)− 249.1.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(O)=O.[Na+].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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)C)cnc1OC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
To a solution of 5-chloro-6-isopropoxy-nicotinic acid isopropyl ester (235 mg, 0.912 mmol) in dioxane (5 mL), 2,4,6-trimethyl-cyclotriboroxane (114 mg, 0.912 mmol), Cs2CO3 (386 mg, 1.19 mmol) and tri-tert.-butylphosphine (7.4 mg, 36 μmol) is added. The mixture is degassed and put under argon before Pd2(dba)3 (17 mg, 18 μmol) is added. The mixture is stirred at 100° C. for 18 h. The mixture is cooled to rt, diluted with water and sat. aq. NaHCO3-solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 9:1 to give 6-isopropoxy-5-methyl-nicotinic acid isopropyl ester (90 mg) as a colourless oil; LC-MS: tR=1.08 min; [M+1]+=238.08; 1H NMR (CDCl3): δ 1.35-1.41 (m, 12H), 2.20 (s, 3H), 5.20-5.30 (m, 1H), 5.37-5.48 (m, 1H), 7.95 (s, 1H), 8.67 (s, 1H). The title compound can be obtained by hydrolising 6-isopropoxy-5-methyl-nicotinic acid isopropyl ester according to the procedure given in step d) of the preparation of 5,6-diisobutyl-nicotinic acid.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[OH:15][C@@H:9]1[CH2:8][N:7]([CH2:6][CH2:5][C@@H:4]([N:16]2[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[CH2:18][CH2:17]2)[CH2:3][OH:2])[CH2:14][CH2:13][C:10]21[CH2:12][CH2:11]2
Reactant: COC(=O)[C@@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1[C@@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 60 %

Procedure:
In analogy to the procedure described in example 2, (R)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4 gave the title compound in 60% yield as a white foam. MS: 456.4 (MH+).