Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCOCC1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN3CCOCC3)cccc2c1Nc1ccccc1C
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide (100 ml) at 100° , then 4-(3-chloropropyl)morpholine hydrochloride (5 0 g, 14 mmol) was added. Heating was continued for 2.5 hours, then the mixture was diluted with water and extracted with ether. The combined extracts were dried and evaporated to an oily residue. Chromatography (silica gel, 3% methanolic ammonia in chloroform) and crystallisation from petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-morpholinopropoxy)quinoline (2.6 g, 58 %), m.p. 111°-113°.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[C:19](=[O:30])[CH2:18][NH:17]1)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>CN(C)C=O>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[C:2]1[N:17]1[CH2:18][C:19](=[O:30])[N:20]2[CH2:29][CH2:28][C:27]3[C:22]([CH:21]2[CH2:16]1)=[CH:23][CH:24]=[CH:25][CH:26]=3
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: O=C1CNCC2c3ccccc3CCN12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CC(=O)N3CCc4ccccc4C3C2)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (313 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 4 hour and stood overnight. Ice-water was added to the solution and resulting precipitate was collected by filtration and washed with water and then dried to afford 2-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (555 mg, 96%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:13].[C:14](OC(=O)C)(=O)[CH3:15]>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:14]([CH3:15])[S:13][C:3]=2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: COc1cc(C(=O)O)cc(S)c1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2sc(C)nc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
4-Amino-3-mercapto-5-methoxybenzoic acid (500 mg) was dissolved in tetrahydrofuran (15 ml) and cooled at −78° C. Acetic anhydride (0.26 ml) was added thereto, and the mixture was warmed over 30 minutes to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (550 mg, Y.:99%) as white crystals.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)=O.[F:19][C:20]([F:31])([F:30])[C:21]([O:23]C(=O)C(F)(F)F)=[O:22]>>[F:19][C:20]([F:31])([F:30])[C:21]([O:23][CH2:1][S:2][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)CC(C)C(=O)c1ccc(S(C)=O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)CC(C)C(=O)c1ccc(SCOC(=O)C(F)(F)F)cc1

Procedure:
A solution of the sulfoxide from Step C of this Example (10 g) in trifluoroacetic anhydride (50 ml) was heated at 45° C. for 25 minutes and the mixture was evaporated, and then coevaporated with toluene, to dryness to give the title compound as an oil (15 g, crude) which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25]C)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.Cl[C:29]1C=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.CNC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:29])[CH3:25])=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Agent: CNC
Product: CN(C)c1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and dimethylamine. M/e+ 380 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=6.9 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (d, J=6.9 Hz, 1H), 6.86 (t, J=6.6 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 5.63 (d, J=7.7 Hz, 1H), 5.56 (s, 2H), 3.18 (s, 3H), 2.96 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[C:15](=[O:33])[N:16]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:17](=[O:25])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[C:19]1([C:18]2[C:17](=[O:25])[N:16]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:15](=[O:33])[C:14]=2[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: O=C1C(Nc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
4-(Trifluoromethoxy)aniline (0.94 mmol, 177 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was sequentially subjected to microwave heating single node 140° C. for 20 min, 140° C. for 120 min, and 140° C. for 120 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 92 mg (45%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.52 (dd, 1H), 7.95 (bs, 1H), 7.80-7.74 (m, 1H), 7.37-7.32 (m, 1H), 7.19-7.08 (m, 3H), 7.01-6.95 (m, 2H), 6.94-6.88 (m, 2H), 6.84-7.78 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>CO.O>[Cl:30][C:26]1[CH:25]=[C:24]([C@@H:22]([OH:23])[CH2:21][NH:20][CH2:19][CH2:18][NH:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of the (R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester (4.12 g) in methanol (60 mL) was added a solution of lithium hydroxide monohydrate (2.08 g) in water (20 mL). The mixture was stirred for 16 h, and 1 N hydrochloric acid was added until the mixture was neutral. The mixture was decanted and the residue was purified by flash silica chromatography eluting with 6:2:0.1 chloroform/methanol/ammonium hydroxide to afford a viscous oil. Trituration with ether and washing with water afforded the title compound as a white solid (2.22 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH:5]([CH2:9][NH2:10])[N:4]1CC1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH:5]([CH2:9][NH2:10])[NH:4]1
Reactant: NCC1COCC(CN)N1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCC1COCC(CN)N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,5-Bis-aminomethyl-4-benzylmorpholine (1.3 g, 5.5 mmol) was dissolved in methanol (50 ml). Ammonium-formiate (1.4 g, 22 mmol) and palladium on activated carbon (10%, 5 g) were added. The reaction mixture was stirred at 50° C. under nitrogen for 3 hours. The catalyst was then filtered off and washed with several small portions of methanol and the solution evaporated to dryness. The tri-amine was used direcly in the next reaction step. FAB/MS: 146 (M+1).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Cl:18][C:19]1[N:24]=[C:23]([NH2:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27].CCN(CC)CC>ClCCl>[Cl:18][C:19]1[N:24]=[C:23]([NH:25][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27]
Reactant: Cc1cc(N)nc(Cl)c1C
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (676 mg, 2.6 mmol) and 6-chloro-4,5-dimethylpyridin-2-amine (314 mg, 2.0 mmol), dichloromethane (7.0 mL) and Et3N (835 μL, 6 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with 1N HCl (3×) and saturated aqueous NaHCO3 (3×). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (560 mg, 73%). ESI-MS m/z calc. 380.07. found 381.3 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[ClH:39]>C(Cl)Cl.CO.[Pd]>[ClH:39].[ClH:39].[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CNCC2
Reaction time: 3 h

Procedure:
To a solution of benzyl 3-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 12) (0.100 g, 0.194 mmol) in CH2Cl2 (2 ml) and methanol (2 ml) was added 10% Pd/C (10.30 mg, 9.68 mmol) followed by HCl (0.024 ml, 0.290 mmol). The mixture was shaken under H2 (50 psi) for 3 h. Celite was added and the mixture was filtered over Celite rinsing with MeOH. Concentration gave a residue which was then dissolved in MeOH and re-filtered then concentrated. The residue was triturated with Et2O and the solids were collected by filtration to give methyl 2-(tert-butoxy)-2-(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate 2 HCl as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.44 (t, J=8.44 Hz, 2H), 7.24 (dd, J=6.85, 18.34 Hz, 2H), 5.08 (s, 1H), 4.10-4.26 (m, 1H), 3.70-3.85 (m, 4H), 3.57-3.70 (m, 2H), 3.21-3.31 (m, 2H), 2.66 (s, 3H), 2.47 (s, 3H), 0.99 (s, 9H). LCMS (M+H) calcd for C23H31N2O3: 383.21. found: 383.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(O)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[NH2:26][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 112.6 %

Procedure:
To 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (313 mg, 0.753 mmol) was added ammonium hydroxide (2 mL, 51.4 mmol) and 1,4-Dioxane (1 mL) to a 5 mL microwave vial and heated in microwave for 20 min. at 100° C. After total of 35 minutes the reaction was completed. The reaction was concentrated to give 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (336 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.60 (s, 1H), 4.71 (tt, J=5.40, 10.64 Hz, 1H), 4.08 (br. s., 2H), 2.91 (br. s., 2H), 1.81-1.94 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C1(N[N:8]=[C:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C=CC=CC=1.C([O-])(=O)C.[Na+].[C:23]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C.[Zn]>[CH3:16][C:15]1[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCCCCC1
Reactant: CCOC(=O)C(=NNc1ccccc1)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(c1C)CCCCC2
Temperature: 80 °C
Yield: 14 %

Procedure:
Ethyl 2,3-dioxobutanoate-2-phenylhydrazone (20.9 g) (T. D; Lash et al., J. Org. Chem. 1992, 57, 4809-4820) in acetic acid (50 ml) was added dropwise to a stirred solution of sodium acetate (10 g), and cycloheptanone (10 g) in acetic acid (100 ml) at 60° C. over 30 minutes. Throughout the addition, small portions of zinc dust (30 g) were added. The reaction was stirred for an additional hour at 80° C., then poured into ice-water (500 g). The resulting solid precipitate was filtered and recrystallised from ethanol to give the product as white needles (2.77 g, 14%), NMR d(CDCl3) 1.38 (3H, t), 1.60-1.95 (6H, m), 2.24 (3H, s), 2.48 (2H, t), 2.68 (2H, t), 4.30 (2H, q), 8.70 (111, bs); M/z (+) 222 (MH+), 176.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-(tert-butyl)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, mp: 167-168° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1HNMR (400 MHz, DMSO-d6): δ 7.77 (d, 1H, J=1.38 Hz), 7.55 (d, 2H, J=8.56 Hz), 7.52-7.51 (m, 2H), 7.43 (d, 1H, J=8.40 Hz), 7.36 (d, 1H, J=8.55 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.40 Hz), 6.51 (d, 1H, J=3.05 Hz), 5.38 (s, 2H), 1.30 (s, 9H), and 1.21 ppm (s, 9H). Elemental Analysis for C29H33N.0.3 H2O: Calculated: C, 86.87; H, 8.46; N, 3.49. Found: C, 87.08; H, 8.51; N, 3.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][N:24]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:23]=2)[C:17]=1[F:39])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:36]1[CH2:35][CH2:34][CH:33]([N:24]2[CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:22]([C:18]3[C:17]([F:39])=[C:16]([N:12]([CH2:13][O:14][CH3:15])[S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:21]=[CH:20][CH:19]=3)=[N:23]2)[CH2:38][CH2:37]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: COCN(c1cccc(-c2nn(C3CCNCC3)cc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: COCN(c1cccc(-c2nn(C3CCN(C(C)=O)CC3)cc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 2,5-difluoro-N-[2-fluoro-3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-methoxymethyl-benzenesulfonamide (135 mg, 0.242 mmol) (prepared as described in Example 2) in DCM (2 mL) triethylamine (0.040 mL, 0.290 mmol, 1.2 eq) was added, followed by acetylchloride (0.019 mL, 0.266 mmol, 1.1 eq) and the solution was stirred at r.t. for 2 h. The reaction mixture was then diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH 97:3) affording 81 mg (56%) of N-{3-[1-(1-Acetyl-piperidin-4-yl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzene-sulfonamide. This intermediate was then treated with a 9:1 TFA/water mixture (1 mL) and stirred at 60° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, then taken up with AcOEt and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5) affording 9 mg of the title compound. HPLC (254 nm): Rt: 5.22 min; 1H NMR (DMSO-d6) Shift: 10.66 (br. s., 1H), 8.48 (s, 1H), 8.38-8.43 (m, 2H), 7.51-7.60 (m, 1H), 7.40-7.49 (m, 2H), 7.29-7.38 (m, 2H), 7.21-7.27 (m, 1H), 7.11 (d, J=6.0 Hz, 2H), 4.44-4.55 (m, 2H), 3.90-3.96 (m, 1H), 3.17-3.28 (m, 1H), 2.69-2.78 (m, 1H), 2.07-2.18 (m, 2H), 2.04 (s, 3H), 1.91-1.99 (m, 1H), 1.74-1.84 (m, 1H); HRMS (ESI) calcd for C27H25F3N5O3S [M+H]+ 556.1625. found 556.1620.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].N1C=CC=CC=1.[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:31])[CH3:30])[C:27]([CH:32]=O)=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:30])[CH3:31])[C:27]([CH:32]=[N:4][O:2][CH3:3])=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CON
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
Methoxylamine hydrochloride (340 mg, 4.07 mmol) and pyridine (322 mg, 4.07 mmol) was added to a solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 250 mg, 0.814 mmol) in EtOH (10 ml) and the mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue triturated with water. The solid product was collected by filtration and dried at 50° C. under vacuum to give the title compound (248 mg, 91%) as a white crystalline solid. NMR (CDCl3): 1.54 (d, 6H), 4.07 (s, 3H), 5.65-5.80 (sept, 1H), 6.95 (d, 1H), 7.15 (m, 2H), 7.34 (t, 2H), 7.50 (s 1H), 7.57 (d, 2H), 8.28 (s, 1H), 8.41 (d, 1 H); m/z 337.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[Si:26]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([CH2:44]O)=[C:39]([F:46])[CH:38]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:26]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([F:46])[C:40]([CH2:44][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:41]([F:43])[CH:42]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(CO)c(F)c1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 16 h
Yield: 66 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (136 mg, 0.36 mmol, 1.0 eq), (4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorophenyl)methanol (115 mg, 0.36 mmol, 1.0 eq) and triphenylphosphine (140 mg, 0.54 mmol, 1.5 eq) in dry THF (2 mL) was added diisopropylazodicarboxylate (0.1 mL). After stirring 16 h, the reaction mixture was concentrated and purified by chromatography (silica, 0-50% EtOAc/Hex) to afford 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (161 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.11 (d, J=7.9 Hz, 1H), 6.76 (dd, J=8.9, 7.8 Hz, 2H), 6.39-6.23 (m, 6H), 4.61 (s, 2H), 3.94-3.80 (m, 4H), 3.69 (s, 3H), 1.45 (s, 6H), 1.26-1.15 (m, 3H), 0.81 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:25]([C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:12][CH2:13]1
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 4-nitro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-methyl-4-nitro-benzenesulfonamide, MS: 451 (MH+).