Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: CCO
Reactant: Cc1ccsc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sccc1C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 3-methylthiophene-2-carboxylic acid (5.00 g, 35.17 mmol) in ethanol (50 mL) was added thionyl chloride (2.60 mL, 35.62 mmol). The resulting reaction mixture was stirred at reflux for 16 h, and allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (3×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 3-methylthiophene-2-carboxylate as light yellow liquid (5.96 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=5.0 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[OH:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][NH2:24]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20][CH2:19][OH:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN(CCO)CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCN(CCO)CCO)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
5 g of para-fluoronitrobenzene were added to a solution of 60 ml of N-methylpyrrolidinone, 6.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 4.3 g of triethylamine. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water, and then dried over P2O5. 7.5 g of 2-[[2-(4-nitrophenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (19) were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][NH:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH2:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:18]([N:16]3[CH2:17][CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:7])[CH2:9][CH2:10]4)[CH2:15]3)=[O:19])[CH:21]=2)[CH2:26]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCN(Cc1ccccc1)C2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH2Cl2 and H2O, and pH of the water layer was adjusted to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H+) 502.0.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][CH2:23][CH:22]([CH3:27])[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCCC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-methylpentylamine (Example 433, Part A) (0.272 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the sasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.335 g, 36.5%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+, found 359.2087, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]2=[O:19])=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC=C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) (55 mg) in DCM (4 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (51 mg), HOBt-hydrate (71 mg), EDAC.HCl (61 mg) and N-methyl morpholine (34 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (82 mg, 80%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:7][CH2:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:22].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:15]1([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:11]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:31][C:32]4[C:37]([N:38]=3)=[CH:36][CH:35]=[CH:34][N:33]=4)=[O:22])[N:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCN1CCCC1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Pyrrolidine (88 μL, 1.06 mmol) was added to a solution of 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.53 mmol) and AcOH (127 mg, 2.1 mmol) in dichloroethane (DCE) (10 mL). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (449 mg, 2.1 mmol) was added and stirring continued for 16 h. The reaction mixture was poured into sat aq NaHCO3 and extracted with DCM. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with CH2Cl2/MeOH+1% TEA(0-10% gradient) to give the title compound (87 mg, 31% yield). MS Calcd for C29H27N5OS2: 525.17. Found (M+H)+ m/z=526.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH:11]1([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)[N:17]=2)[CH2:13][CH2:12]1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.[BH3-]C#N.[Na+]>>[CH:11]1([NH:14][C:15]([C:16]2[N:17]=[C:18]([C:22]3[CH2:23][CH2:24][N:25]([CH2:36][C:35]4[CH:38]=[CH:39][C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:33][CH:34]=4)[CH2:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:13][CH2:12]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cccc(C2=CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)n1
Reaction time: 12 h
Yield: 23 %

Procedure:
1′-(4-Trifluoromethoxybenzyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (9) was prepared by adding diisopropyl ethyl amine to a suspension of compound 5 (72 mg, 0.25 mmol), 4-trifluoromethoxybenzaldehyde (8) (Aldrich) and 3 Å molecular sieves (200 mg, Aldrich). The mixture was stirred for 12 hours and NaCNBH3 was added. The crude product was filtered and then purified on Prep TLC (10% MeOH in dichloromethane with 1% NH4OH) to provide the title compound 9 (25 mg, yield 23%): 1H NMR (400 MHz, CD3OD, HCl-salt): δ 8.48 (bd, 1 h, NH), 7.88 (d, 1H, J=7.6 Hz), 7.83 (t, 1H, J=7.6 Hz), 7.65 (d, 1H, J=7.6 Hz), 7.57 (m, 2H), 7.32 (d, 2H, J=8.8 Hz), 6.68 (m, 1H), 4.39 (m, 2H), 3.85 (m, 2H), 3.68 (m, 1H), 3.26 (m, 1H), 3.12 (m, 1H), 2.82 (m, 1H), 2.71 (m, 1H), 0.72 m, 2H), 0.54 (m, 2H); MS: 418.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1)=[O:30]
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) (0.23 g, 1.18 mmol, 1 eq) was dissolved in dichloromethane and DIPEA (2.5 eq), under nitrogen, and 2-chlorobenzoic acid chloride (0.15 ml, 1.18 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 3:1) and the desired product (R)-methyl 1-(2-chlorobenzamido)-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate (B-28) was thus obtained. Yield: 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC(OC)=CC=1.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[OH:9][C:8]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a suspension of 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol (25 mg, 0.055 mmol) in 1.5 ml of dichloromethane was added 78 mg of PS-thiophenol resin (Argonaut Technologies, 1.41 mmol-g−1), followed by TFA (0.3 ml). The clear suspension was stirred at room temperature for 1 hour, then the resin was filtered off, washed with ethyl acetate, then methanol. The filtrate was evaporated and the residue was taken up in 2 ml of ethyl acetate and saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered off, washed with water, then ethyl acetate and dried in vacuo to afford 5-(5-(4-hydroxy-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ol as a light beige solid (15 mg, 80% yield). 1H NMR (DMSO-d6): δ 11.83 (broad s, 1H), 11.67 (broad s, 1H), 9.05 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.88 (dd, J=3.0, 9.5 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.71 (d. J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (dd. J=2.0, 8.5 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.44 (d, s 9.0 Hz, 1H), 3.86 (s, 3H); HPLC/MS m/z: 334.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:26][C:27](=[CH2:31])[C:28](Cl)=[O:29]>C(OCC)C>[F:26][C:27](=[CH2:31])[C:28]([O:18][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[O:29]
Reactant: C=C(F)C(=O)Cl
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccc(C)c(C)c1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.4 %

Procedure:
A solution of 27.3 g (0.1 mol) Of 2-(3,4-dimethylphenyl)hexafluoro-2-propanol and 10.1 g (0.1 mol) of triethylamine in 50 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 50 ml of dry diethyl ether in the course of 35 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 17.7 g (51 percent of theory) of 2-(3,4-dimethylphenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 72° to 73° C. (under 0.4 mbar) were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:4]1[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:2]=2[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, bis(3,5,3′,5′-dimethoxy-dibenzylideneacetone) palladium (0) (6% mol, 1.1 mmol, 0.9 g), 1,1′-bis(diphenylphosphino)ferrocene (6% mol, 0.61 g), NatBuO (2 eq., 36 mmol, ˜3.5 g), were all dissolved in 1,4-dioxane (40 ml) and the system was purged through with argon. The mixture was stirred at room temperature for 15 minutes and 1,1-dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate (D32) (7.7 g, 17.9 mmol) was added at room temperature and the mixture was heated to 80° C. for 1.5 hours and then to 100° C. for extra 2 hours; the mixture was then cooled to room temperature, diluted with ethyl acetate and the organic phase obtained was washed with water and brine. Organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product that was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 4.3 g, 70%, pale-grey solid, M+−H=348.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([OH:15])[CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(C)c(Cc2cccc(O)c2C=O)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C=O)c(OC)c(OC)c1OC
Yield: 94.4 %

Procedure:
6-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (187 mg, 0.54 mmol) was dissolved in acetone (20 ml) and after adding thereto anhydrous sodium carbonate (149 mg, 1.08 mmol) and benzyl bromide (120 mg, 0.70 mmol), the solution was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (221 mg, 0.51 mmol, 94%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: OC(c1ccc(F)cc1F)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (1.69 mmol) of the compound from Example 8A and 312 mg (1.69 mmol) of the compound from Example 154A in analogy to the synthesis of the compound from Example 227. 170 mg (29% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ClCCl.CO.N>>[N:19]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [5-(4-chlorophenyl)pyridin-2-yl]propynoic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.2 g (48% of theory); C26H24ClN3O (M=429.95); calc.: molecular ion peak (M+H)+: 430/432; found: molecular ion peak (M+H)+: 430/432; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC[C@@H](OCc4ccccc4)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 100.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (137 mg, 0.194 mmol) prepared in Example 112b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (108 mg, 70%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:38])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][NH:33][CH2:32][CH2:31][C:30]=3[N:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1.[CH2:39]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:38])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][N:33]([CH3:39])[CH2:32][CH2:31][C:30]=3[N:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1
Reactant: C=O
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)c2ccc3c(n2)CCNC3)C1
Agent: Cl
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)ccc2C1

Procedure:
In a manner similar to that employed in Example 18, the title compound was prepared from the compound obtained in Example 341 and formalin.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([NH:38][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[CH:35]([CH3:37])[CH3:36]
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 mg (1.05 mmol) of CDI were added to a solution of 323 mg (1.00 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (16 ml), and the mixture was stirred for 1 hour at RT. 99 μl (1.00 mmol) of isobutylamine were then added, and stirring was continued for a further 5 days at RT. The reaction solution was then washed in each case twice with a 4 M aq. ammonium chloride solution and a 1 M aq. sodium hydrogen carbonate solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was taken up in ethyl acetate (30 ml) and washed with 0.4 M hydrochloric acid (5 ml). The organic phase was again dried over MgSO4, filtered and concentrated in vacuo. 160 mg (0.42 mmol, 42 of N-(isobutyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue. MS: m/z 379.1 [M+H]+