Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33](O)=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH2:19][CH2:20][CH3:21]>>[CH3:17][CH:18]([N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.20 g of compound 16 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.63 g of ethyl 4-(2-aminophenoxy)butyrate and 1.60 g of 3-[1-(1-methylbutyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:25]=[C:26](/[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)\[CH3:27])[C:9]=2[CH:10]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: CN1CCc2[nH]c3cc(F)ccc3c2C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccc(F)cc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.98 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (18 mg, 0.09 mmol) L-proline (22 mg, 0.19 mmol) and potassium phosphate (410 mg, 1.96 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (250 mg, 1.17 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.76 (m, 2H), 7.50 (m, 1H), 7.30 (t, 2H), 7.10 (d, 2H), 7.0 (t, 1H), 4.30 (m, 2H), 3.0 (s, 3H), 2.80 (m, 4H), 1.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=2[CH3:1])[C:6]([NH:8][CH:9]2[C:14]([CH3:15])([CH3:16])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])(=[O:23])=[O:22])[CH2:25][CH2:26]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCN(S(C)(=O)=O)CC1
Yield: 44 %

Procedure:
Compounds 32 was prepared from 117 mg 29 by stirring in 5 mL dry dichloromethane adding 100 μl N,N-diisopropylethylamine and 20 μl methyl sulfonyl chloride overnight at room temperature. After aqueous work-up the product was isolated by preparative HPLC chromatography and 48 mg of an off white solid was obtained (44% yield). MS (M−1)=496.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:25][CH:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:52]>CO.O1CCOCC1.ClCCCl>[ClH:1].[ClH:52].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:25][CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCNC2CCNC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.101 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The pale orange powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a pale orange powder (0.033 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[CH:3]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(F)ccc2c1
Solvent: ClCCl
Product: Oc1ccc2cc(F)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A flask was charged with 2-fluoro-6-methoxynapthalene (3.80 g, 21.6 mmol) and dichloromethane (86 mL) and cooled to 0° C. in an icebath under a flow of nitrogen. A solution of borontribromide (26 mL of a 1M solution in dichloromethane, 25.9 mmol) was added via cannula. The reaction solution was stirred 15 minutes at 0° C., the cooling bath was removed and the reaction was stirred for 1.5 h at ambient temperature. The reaction was quenched by slowly adding excess 10% aqueous hydrochloric acid. The two-phased reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed (2x, brine), dried (Na2SO4), filtered and concentrated in vacuo to afford a brown gummy solid. Purification by flash chromatography (silica gel; 20% ethyl acetate/hexane) afforded the desired product (3.63 g, 91% yield). Recrystallization from cold ether/hexanes provided the title compound as a colorless powdery solid. mp 118°-120° C.; 1HNMR (300 MHz, DMSO-d6) δ 7.11-7.18 (m; 2H), 7.30 (td; J=9,9,3 Hz; 1H), 7.55 (dd; J=10.5,3 Hz; 1H), 7.73-7.79 (m; 2H), 9.73 (s; 1H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12]C)[C:4]=2[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[CH3:12][N:11]1[C:4]2[CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
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: CCO
Product: Cn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 140 °C
Yield: 109.5 %

Procedure:
A microwave reaction vial was charged with 6-chloro-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.08 mmol), 4-(trifluoromethyl)phenylboronic acid (20 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (5.06 mg, 0.004 mmol), and 2M aqueous sodium carbonate solution (0.13 mL) in ethanol (2 mL). The vial was sealed and then heated in a microwave at 140° C. for 10 min. At this time, the resulting mixture was filtered through a pad of Celite® and concentrated in vacuo. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-methyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (25.6 mg, 39.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.8 (s, 3H) 6.5 (d, J=3.01 Hz, 1H) 7.0 (s, 1H) 7.1 (d, J=3.01 Hz, 1H) 7.8 (d, J=8.28 Hz, 2H) 8.0 (d, J=8.28 Hz, 2H) 11.1 (br. s., 1H). LC-MS calcd. for C15H12F3N2O [(M+H)+] 293, obsd. 293.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:57]3[CH2:56][CH2:55][N:54]([CH2:53][CH:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)[CH2:59][CH2:58]3)=[O:22])[N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (100 mg, 0.28 mmol), EDCI (75 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) DIPEA (0.06 mL, 0.33 mmol), 1-(1-methyl-piperidin-4-ylmethyl)-piperazine (66 mg, 0.33 mmol) and DCM (10 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: NC=O
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of 5-bromo-2-aminobenzoic acid (7.9 g, 36.6 mmole) in N-methylpyrrolidinone (20 ml) was added formamide (7.25 ml, 182.5 mmole). The reaction mixture was heated at 150° C. for 7 hours, cooled to room temperature, poured into water (400 ml) and stirred for 15 minutes. The resulting suspension was filtered through a sintered glass funnel to collect the precipitate. The solid was dried under vacuum for 16 hrs to give 7.0 g of a tan solid. The resulting compound was characterized as follows: mass spectrometry: M/Z 226; HPLC: method A, retention time (Rt) 1.51 minutes).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15](=O)[NH:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15]([Cl:32])=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Cl)c12
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of (4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl)-acetic acid ethyl ester (1.78 g, 6.17 mmol, 1 equiv, from step 3) in toluene (15 mL) were added diisopropylethylamine (1.18 mL, 6.79 mmol, 1.1 equiv) and phosphorous oxychloride (0.63 mL, 6.79 mmol, 1.1 equiv) at 0° C. under argon. The flask was equipped with a reflux condenser and heated at 80° C. for 5 h. The reaction mixture was cooled to rt and quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (20% EtOAc/hexane) to yield 1.12 g (3.6 mmol, 56%) of a light yellow solid. 1H-NMR (DMSO-d6) δ 9.01 (s, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.15 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 4.10 (q, 2H), 3.92 (s, 2H), 1.20 (t, 3H), LCMS RT=3.19 min, [M+H]+=307
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
2-(2-Hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (229 mg) obtained from Referential Example 77 and triethylamine (209 μL) were dissolved in methylene chloride (5 mL) To the resultant solution, methanesulfonyl chloride (116 μL) was added at room temperature, followed by stirring for 30 minutes. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and methylene chloride. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound in the form of crystals (288 mg, 93%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[CH2:21][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: BrCc1cc2ccccc2o1
Product: c1ccc(Oc2ccc(C3CCN(Cc4cc5ccccc5o4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethylbenzofuran to produce the above.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 60 °C
Yield: 70.8 %

Procedure:
To a solution of 2-Chloromethyl quinoline (2.5 g, 14 mmole) in acetone (47 ml) was added 4-hydroxy acetophenone (1.92 g, 1.0 eq.) and potassium carbonate (2.5 g, 2 eq.). The reaction mixture was heated at 60° C. for 16 h under N2 atmosphere, cooled to ambient temperature and poured into 1N sodium hydroxide (50 ml)/ethyl acetate (100 ml). The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Biotage MPLC was run using a 5-40% ethyl acetate/hexane gradient on a 40 M column to provide the title compound as a white solid (2.75 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7, 1H), 7.91 (m, 2H), 7.82 (dd, J=8.3, 1.3 1H), 7.73 (t, J=7.1 Hz, 1 H), 7.62 (d, J =8.3 Hz, 1 H), 7.54 (t, J=7.1 Hz, 1 H), 7.06 (m, 2H), 5.42 (s, 2 H), 2.51 (s, 3 H); MS: (M+H m/z=278.3).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:23]3[C:24]([F:44])=[C:25]([N:29]([CH2:41][O:42][CH3:43])[S:30]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=3)=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([N:20]1[CH2:19][CH2:18][CH:17]([N:15]2[CH:16]=[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)[C:13]([C:23]3[C:24]([F:44])=[C:25]([N:29]([CH2:41][O:42][CH3:43])[S:30]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=3)=[N:14]2)[CH2:22][CH2:21]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: COCN(c1cccc(-c2nn(C3CCNCC3)cc2-c2ccnc(NC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: COCN(c1cccc(-c2nn(C3CCN(C(C)=O)CC3)cc2-c2ccnc(NC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of N-{3-[4-(2-tert-Butylamino-pyridin-4-yl)-1-piperidin-4-yl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.159 mmol) (prepared as described in example 8) in DCM (1.5 mL) triethylamine (0.024 mL, 0.175 mmol, 1.1 eq) was added, followed by acetylchloride (0.011 mL, 0.159 mmol, 1 eq) and the solution was stirred at r.t. for 1 h. The reaction mixture was then diluted with DCM and washed with water. The aqueous phase was back extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH/NH3 7N in MeOH 94.5:1) affording 93 mg (87%) of N-{3-[1-(1-Acetyl-piperidin-4-yl)-4-(2-tert-butylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide, HPLC (254 nm): Rt: 6.59 min; 1H NMR (DMSO-d6) Shift: 8.18 (s, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.58-7.66 (m, 1H), 7.45-7.58 (m, 3H), 7.23-7.35 (m, 2H), 6.26 (s, 1H), 6.15 (dd, J=1.1, 5.4 Hz, 1H), 5.76 (br. s., 1H), 5.01 (s, 2H), 4.43-4.56 (m, 2H), 3.89-3.97 (m, 1H), 3.30 (s, 3H), 3.17-3.25 (m, 1H), 2.69-2.78 (m, 1H), 2.02-2.16 (m, 2H), 2.05 (s, 3H), 1.94 (qd, J=4.6, 12.1 Hz, 1H), 1.79 (qd, J=4.5, 12.1 Hz, 1H), 1.31 (s, 9H); HRMS (ESI) calcd for C33H38F3N6O4S [M+H]+ 671.2622. found 671.2623.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1nccc2ncccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF (40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was then poured into water (120 mL). The aqueous phase was extracted with EtOAc (150 mL×4). The combined organic layers were washed with brine (100 mL×3), dried over sodium sulfate, and concentrated under reduced pressure to give 3.4 g of the crude product as a brown solid. ESI MS: m/z 172 [M+H]+.
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][NH:9][C:10]([C:12]1([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(NOCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NO)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Yield: 7.1 %

Procedure:
A solution of 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid N-benzyloxyamide(11.28 grams, 0.0225 mole) in ethyl acetate (600 mL) was treated with 5% palladium on barium sulfate (5.0 grams) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 18 hours. After filtration through nylon (pore size 0.45 mm) to remove the catalyst, the filter pad was rinsed with methanol. Combined filtrate and rinse were evaporated and the residue taken up in hot methanol. Cooling afforded crude 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid hydroxyamide (5.941 grams, 64%, mp 176-177° C.) as a white crystalline solid. The mother liquor was evaporated and the residue crystallized from 50% methanoldichloromethane to give additional 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid hydroxyamide (0.660 grams, mp 184-185° C.) as white needles. The mother liquor was again evaporated and the residue crystallized from methanol/dichloromethane to give additional product (1.861 grams, mp 176-177° C.). Recrystallization of the first lot from methanol/dichloromethane provided analytically pure 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide (3.091 grams, mp 184-185° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:22])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow oil (0.405 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([C:8](=[O:27])[CH:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])=[CH:15][C:14]=2[F:26])C([O-])=O)[N:5]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:4]=1)#[N:2].CO.S(O)(O)(=O)=O.C(=O)([O-])O>C(OCC)(=O)C>[F:26][C:14]1[CH:15]=[C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=[O:25])[CH:17]=[CH:18][C:13]=1[CH2:9][C:8]([C:6]1[N:5]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:4]=[C:3]([C:1]#[N:2])[CH:7]=1)=[O:27]
Reactant: COc1ccc(-n2nc(C#N)cc2C(=O)C(C(=O)[O-])c2ccc(-n3ccccc3=O)cc2F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-n2nc(C#N)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 23 °C
Reaction time: 96 h
Yield: 83.4 %

Procedure:
Part H. To 3-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-oxopropanoate (100 mg, 0.210 mmol) was added methyl alcohol (1.5 mL) and 4M aqueous dihydrogen sulfate (0.50 mL). The reaction was then warmed to reflux. After 4 days, the reaction was cooled to 23° C., and the resulting white suspension was poured into saturated aqueous hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to afford 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (75 mg, 85%) as a pale yellow oil. LC/MS (ESI+): 429.0 (M+H)+.