Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccnc(/C=C/c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(CCc2ccc(F)cc2)c1
Reaction time: 18 h
Yield: 100.1 %

Procedure:
(E)-methyl 2-(4-fluorostyryl)isonicotinate (3.6 g, 13.99 mmol) was dissolved in methanol (200 mL). Palladium on charcoal (0.149 g, 1.40 mmol) was added and the mixture was hydrogenated at atmospheric pressure and room temperature for 18 h. The catalyst was filtered off and the filtrate was evaporated. Methyl 2-(4-fluorophenethyl)isonicotinate (3.63 g, 99%) was isolated. MS m/z 260 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([N:23]2[C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=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(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1ccnn1-c1ccccc1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccnn4-c4ccccc4)CC3C2)n1
Yield: 72.6 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 2-phenyl-2H-pyrazole-3-carboxylic acid (56.9 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (79.0 mg, 74%). MS (ESI) mass calcd. for C22H24N6O, 388.47; m/z found 389.2 [M+H]+. 1H NMR (CDCl3): 7.67 (d, J=1.7, 1H), 7.50 (d, J=7.4, 2H), 7.37 (t, J=7.8, 2H), 7.29-7.23 (m, 1H), 6.56 (d, J=1.7, 1H), 6.30 (s, 1H), 3.86-3.71 (m, 2H), 3.70-3.51 (m, 2H), 3.43-3.22 (m, 3H), 3.05-2.77 (m, 3H), 2.29 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:3](OCC)[O:4]CC.O1CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:3]=[O:4]
Reactant: CCOC(OCC)C(C)C=CC=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 14.0 g 2,6,10-trimethyl-1,1-diethoxy-3,5,9-undecatriene (2D, 0.05 mol), 100 mL tetrahydrofuran and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and further 24 h of stirring at 20-25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 in 20 mL water was added for neutralization. Removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL of water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.3 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]1.CO.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O>[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH3:14])[CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:17]1
Reactant: O=C1CCN(C(=O)C2CC2)CC1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H]1CNCCN1C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.4 %

Procedure:
To a mixture of (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 1.1 mmol) and 1-(cyclopropylcarbonyl)piperidin-4-one (150 mg, 0.9 mmol) in methanol (5 mL, 120 mmol) was added slowly trifluoroacetic acid (6.9 μL, 0.09 mmol) followed by sodium cyanoborohydride (56 mg, 0.9 mmol). The reaction mixture was stirred overnight at RT, concentrated by rotary evaporation, washed with 1 N NaOH (20 mL) and extracted with EtOAc (3×15 mL). Combined organic fractions were washed with brine, dried with sodium sulfate, and concentrated by rotary evaporation to afford a white solid (320 mg). A mixture of the white solid in 4 M HCl in 1,4-dioxane (5 mL) was stirred at RT for 30 min and concentrated to provide the di-HCl salt of the title intermediate (180 mg, 62% yield) as a white suspension.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11]([NH:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
2,4-Bis-benzyloxy-5-bromobenzoic acid (13.5 g, 33 mmol) was dissolved in DMF (anhydrous, 100 ml), and carbonyldiimidazole (CDI) (6.1 g, 37 mmol) was added and the resulting solution was stirred at r.t for 2 h. 3-Methoxypropylamine (3.6 g, 40 mmol) solution in DMF (25 ml) was added and the resulting solution was stirred at r.t. until the reaction was complete. The reaction was diluted with water (250 ml), extracted with ethyl acetate (250 ml×3), and the combined organics were washed thoroughly with water to remove DMF and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 2,4-bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (15.8 g, 99%). M.p.: 104-106° C.; 400 MHz 1H NMR (CDCl3) δ: 8.41 (s, 1H), 7.85 (t, J=5.2 Hz, 1H), 7.45-7.32 (m, 10H), 6.53 (s, 1H), 5.14 (s, 2H), 5.09 (s, 2H), 3.47-3.41 (q, J=5.2 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 1.72-1.65 (pent, J=6.4 Hz, 2H); LCMS: 484, 486 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Reactant: Clc1ccc2c(c1)NCC2
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(Cl)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 6-chloroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]([C:9]1(C(OCC)=O)[CH2:23][CH2:22][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][C:11]=2[CH2:10]1)=[O:8])([OH:3])=[O:2].Cl>O>[C:16]1([C:14]2[O:15][C:11]3[CH2:10][CH:9]([C:7]([CH:5]4[CH2:6][CH:4]4[C:1]([OH:3])=[O:2])=[O:8])[CH2:23][CH2:22][C:12]=3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1(C(=O)C2CC2C(=O)O)CCc2nc(-c3ccccc3)oc2C1
Agent: Cl
Solvent: O
Product: O=C(O)C1CC1C(=O)C1CCc2nc(-c3ccccc3)oc2C1

Procedure:
790 mg (2.06 mmol) ethyl 6-(2-carboxy-cyclopropanecarbonyl)-2-phenyl-4,5,6,7-tetrahydro-benzoxazole-6-carboxylate, 5 ml of 32% hydrochloric acid and 5 ml of water are refluxed together for 6 h. The reaction mixture is extracted with DCM, the org. phase is dried on magnesium sulphate and then the solv. is eliminated by rotary evaporation i.V.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1c(C=O)cccc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(OC)c2o1
Yield: 19.5 %

Procedure:
A solution of 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (2.00 g) and potassium tert-butoxide (96 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour under ice-cooling. Water was added to the reaction mixture, and the solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate=7:1, v/v) to give 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]#[C:19][CH2:20][CH3:21])[CH:12]=O.C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[CH:21]
Reactant: CCC#COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 77.3 %

Procedure:
Piperidine (0.19 mL, 1.9 mmol) was added to a suspension of 3-methoxy-4-(but-1-ynyloxy)benzaldehyde (0.39 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.39 g, 1.9 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-(but-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.48 g, 75%) as a yellow crystalline solid; mp 178-180° C.; δH (400 MHz, DMSO-d6) 2.61 (dt, J=6.8, 2.4 Hz, 2H, CH2CCH), 2.86 (t, J=2.4 Hz, 1H, CCH), 3.81 (s, 3H, OCH3), 4.06 (t, J=6.8 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.13 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5,6′=8.0 Hz, 1H, H6′), 7.36 (s, 1H, H2′), 7.53 (d, J=15.6 Hz, 1H, CH═CHCO), 7.58 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.97 (d, J3,4=8.0 Hz, 1H, H3), 8.59 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 19.6, 56.4, 67.2, 73.2, 82.0, 111.5, 113.6, 117.3, 120.8, 121.0, 123.2, 123.3, 128.4, 131.8, 134.7, 141.7, 142.2, 149.8, 150.1, 164.8, 170.1; HRMS (ESI) calculated for C21H19NO5 [M+H]+ 366.1336. found 366.1337; vmax 755, 1263, 1512, 1603, 1689, 3257, 3401 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:23](O)=[O:24])=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:26]([N:29](C(C)C)[CH2:30]C)(C)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.CNC>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O>[CH3:26][N:29]([CH3:30])[C:23]([C:17]1[C:16]2[C:20](=[CH:21][C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:10])=[O:11])=[CH:14][CH:15]=2)[N:19]([CH3:22])[CH:18]=1)=[O:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(C(=O)O)c2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cn(C)c2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
300 mg 6-(3,5-dichloro-phenylsulphonylamino)-1-methyl-1H-indole-3-carboxylic acid are dissolved in 2 ml dimethylformamide, combined with 319 μl N,N-diisopropyl-N-ethyl-amine and 241 mg O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) and stirred for 15 minutes at ambient temperature. 751 μl of a 2 M solution of dimethylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. Then it is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH2:6])=[O:5].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.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([O:69][CH2:70][C:71]([F:77])([F:76])[C:72]([F:75])([F:74])[F:73])[CH:64]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:6][C:67]1[CH:68]=[CH:63][CH:64]=[C:65]([O:69][CH2:70][C:71]([F:76])([F:77])[C:72]([F:74])([F:75])[F:73])[CH:66]=1)=[O:5]
Reactant: FC(F)(F)C(F)(F)COc1cccc(Br)c1
Reactant: NC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(Nc1cccc(OCC(F)(F)C(F)(F)F)c1)c1c(F)cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
Under nitrogen, to 2-fluoro-6-nitrobenzamide (1.15 g, 6.23 mmol, 1.00 equiv) in dioxane (6.2 mL) at 23° C. was added palladium acetate (140 mg, 0.623 mmol, 0.100 equiv), Xantphos (541 mg, 0.935 mmol, 0.150 equiv), cesium carbonate (1.21 g, 8.72 mmol, 1.40 equiv), and 1-bromo-3-(2,2,3,3,3-pentafluoropropoxy)benzene (1.90 g, 6.23 mmol, 1.00 equiv). After stirring for 4 hr at 100° C., the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with EtOAc/hexanes to afford 2.1 g of the title compound (83% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]([S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14])([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH3:28]
Reactant: CI
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1cccc2ccccc12
Yield: 16.7 %

Procedure:
In analogy to example 3.1:1.74 g (4.8 mmol) of (naphthalene-1-sulfonyl)-(3-oxo-cyclohexyl)-acetic acid methyl ester was dissolved in 10 mL of DMF at 0° C. 232 mg (5.3 mmol, 1.1 eq) of NaH (60%) were added and the reaction mixture was stirred 30 minutes before the addition of 1.03 g (7.2 mmol, 1.5 eq) of methyliodide. The reaction was stirred over night, poured on water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with AcOEt/heptane 2:1, yielded 0.30 g (17%) of (RS,SR)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid methyl ester as a white foam MS: 375 (MH+) and 0.42 g (23%) of (RR,SS)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid methyl ester as a white solid MS: 375 (MH+).
Reaction SMILES: COC1([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])C=CC=CC1OC.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[C:24]=1[F:30]>>[F:30][C:24]1[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=1[S:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:14])[CH3:15]
Reactant: Fc1cccc(I)c1F
Reactant: COC1C=CC=CC1(OC)S[Si](C(C)C)(C(C)C)C(C)C
Product: CC(C)[Si](Sc1cccc(F)c1F)(C(C)C)C(C)C

Procedure:
Prepared as described for (1,2-dimethoxy-phenylsulfanyl)-triisopropyl-silane starting from 1,2-difluoro-3-iodobenzene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH3:19])[N:3]=1.O.[NH2:21][NH2:22]>CC#N.CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:22][N:21]=1
Reactant: CCNc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 68.9 %

Procedure:
In a 25 mL flask under argon was added 4-[2-amino-6-(ethylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.164 g, 0.442 mmol) followed by EtOH (3.5 mL). Hydrazine monohydrate (0.87 mL, 17.7 mmol) was added and the reaction mixture was stirred for 6 hours at 80° C. The reaction was cooled to room temperature and concentrated to near dryness. Water (3 mL) was added (orange oil was formed) followed by CH3CN (8 drops), and the mixture was sonicated. A light yellow precipitate was formed. The suspension was cooled on an ice bath and the solid was filtered, washed with water and dried under vacuum at 40° C. to afford the title compound (82 mg, 68%) as a light yellow solid. LC-MS (ES) m/z=270 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, J=7.2 Hz, 3H), 3.20-3.40 (m, 2H), 5.36 (s, 2H), 5.97 (s, 2H), 6.25 (s, 1H), 6.82 (bs, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.84 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31]CC1C=CC(OC)=C(OC)C=1)[C:5]([N:7]([CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[OH:31])[C:5]([N:7]([CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:9]=1[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:6]
Reactant: COc1ccc(COc2ccc(C(=O)N(C)c3ccc(Oc4ccccc4)cc3C(=O)NC(C)C)cc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1N(C)C(=O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 44C (30 mg, 0.05 mmol) in CH2Cl2 (1 mL) at 0° C. was treated with TFA (0.05 mL). The solution was warmed to room temperature and stirred for 16 hours. The crude mixture was purified by chromatography (SiO2, 50% EtOAc in hexane) to afford 44D (15 mg, 68%). HPLC Retention Time=3.09 min (YMC ODSA 5 u C18 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm) [M+H+]=439.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:19][CH2:20][F:21])[C:14]2([CH3:23])[CH3:22])C1C=CC=CC=1>CO.[Pd]>[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:19][CH2:20][F:21])[C:14]2([CH3:23])[CH3:22]
Reactant: CC1(C)c2cccc(N(Cc3ccccc3)Cc3ccccc3)c2C(=O)N1CCF
Agent: [Pd]
Solvent: CO
Product: CC1(C)c2cccc(N)c2C(=O)N1CCF
Reaction time: 16 h

Procedure:
75 mg (0.188 mmol) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 5 bar H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>>[CH3:6][O:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([NH:16][CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1OC
Reactant: O=C(O)CBr
Product: COc1ccc(NCC(=O)O)c([N+](=O)[O-])c1OC
Temperature: 58 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Bromoacetic acid (0.876 g, 6.31 mmol, 0.5 eq) is added portionwise to 3,4-dimethoxy-2-nitro-phenylamine (2.5 g, 12.61 mmol, 1.0 eq) and the mixture is stirred at 58° C. for 16 hours. The reaction is then quenched by 25% ammonia in water and diluted with water. The solid is filtered off and washed with 10% ammonia in water. The combined solutions are acidified by concentrated hydrochloric acid and the resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford (3,4-dimethoxy-2-nitro-phenylamino)-acetic acid as a red solid (1.1 g, 34% yield).
Reaction SMILES: C(OC([N:6]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[CH2:12][C:11](=[O:22])[NH:10][CH:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:7]1=[O:37])=O)C.[OH-].[Na+]>CO>[Cl:36][C:33]1[CH:34]=[C:35]2[NH:6][C:7](=[O:37])[C:8]3([CH:13]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[CH3:21])[CH2:12][C:11](=[O:22])[NH:10][CH:9]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:30]2=[CH:31][CH:32]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cc(F)ccc1C)CC(=O)NC2c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester prepared in example 145c (0.20 g, 0.31 mmol) in methanol (12 mL) was added NaOH (22 mg, 0.56 mmol). The mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous HCl solution (1 N). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and then concentrated. The residue was purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (9 mg).