Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[F:32])[OH:6])[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]=1[F:32])[O:6][CH3:35])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(O)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Product: CCOC(=O)C(OC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F

Procedure:
(RS)-[3-(tert-Butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-methoxy-acetic acid ethyl ester was prepared in analogy to example 173 from (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester and iodomethane. Yellowish oil. MS 484.2 (4, [M+]+); 427.1 (29, [M−tBu]+); 411.2 (14, [M−COOEt]+).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:21])C(=O)C1>>[Cl:21][C:5]1[N:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1cnc(C(=O)OCC)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: CCCc1[nH]c(C(=O)OCC)nc1Cl
Yield: 73.5 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-propyl-1H-imidazole-2-carboxylate obtained in Example (46b) (1.01 g, 5.54 mmol) and NCS (0.74 g, 5.50 mmol), to obtain 876 mg of the title compound as a white solid (73%).
Reaction SMILES: OC(COC1C=CC=CC=1C=CC)CN.[OH:16][CH:17]([CH2:29][O:30][C:31]1[C:40]2[C:35](=C[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH2:18][NH:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2>>[OH:16][CH:17]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:40]=1[CH2:39][CH:38]=[CH2:37])[CH2:18][NH:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Agent: CC=Cc1ccccc1OCC(O)CN
Product: C=CCc1ccccc1OCC(O)CNc1ncnc2[nH]cnc12

Procedure:
By substituting 2-hydroxy-3-(2-propenylphenoxy)propylamine (3.61 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C>[Br:23][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:3]=2[C:2]([F:14])([F:1])[F:15])[NH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Br)c2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.047 g, 0.22 mmol) in DMF (2 mL), under N2, was added a solution of NBS (0.043 g, 0.24 mmol) in DMF (0.5 mL). The mixture was stirred in the ice bath for 30 min and then at rt for 1 h. The mixture was partitioned between Et2O and an aqueous solution of Na2S2O3. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by radial chromatography (5-50% EtOAc-hexanes gradient) to afford the title compound: 1H NMR (400 MHz, CDCl3+few drops of CD3OD) δ 11.52 (bs, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.48-7.45 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35]O)=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.C1(P([N:59]=[N+:60]=[N-:61])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:59]([CH2:35][C:33]1[S:34][C:30]([C:12]2[C:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)[CH:19]=4)[C:14]=3[N:10]([CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:11]=2)=[CH:31][CH:32]=1)=[N+:60]=[N-:61]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CO)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN=[N+]=[N-])s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 382 (8.0 g, 13.2 mmol) in tetrahydrofuran (100 mL) was cooled to about 0° C. and diphenylphosphoryl azide (7.1 mL, 33.0 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7ene (4.9 mL, 33.0 mmol) were added slowly in the dark. After the addition was complete, the mixture was stirred for about 2 hours at ambient temperature in the dark. The mixture was basified by addition of potassium carbonate and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrate. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 632 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][C:24]([F:28])([F:27])[CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Product: Cc1ccccc1C(=O)NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1

Procedure:
From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[N:30](C5CCCCO5)[N:29]=[CH:28][CH:27]=4)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.CCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[CH:27]=[CH:28][NH:29][N:30]=4)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2ccnn2C2CCCCO2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxazole-4-carboxamide (56 mg, 0.111 mmol) was added into a flask under nitrogen atmosphere. 10% HCl/EtOH (0.126 ml, 0.277 mmol) was added and the reaction mixture was stirred in RT for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 1M Na2CO3. The organic phase was dried, filtered and evaporated. The product was triturated using acetonitrile and THF, respectively. Yield 29.6%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.61 (m, 1H), 6.61 (d, 1H), 6.86 (d, 1H), 7.49 (d, 1H), 7.60 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.87 (dd, 1H), 7.92 (d, 1H), 8.23 (s, 1H), 10.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22]C)=[C:16](I)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[CH:17]=[CH:16][C:15](=[O:22])[NH:14][C:13]=3[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccc(=O)[nH]c21
Temperature: 200 °C
Yield: 56.3 %

Procedure:
N-(4-Chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (150 mg) is mixed with pyridine hydrochloride (1.50 g). The resulting solid is heated at 200° C. for 1 h, then cooled to room temperature and washed with MeOH. The residue is then dissolved in CH2Cl2, washed with 1N HCl, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by silica gel chromatography (CH2Cl2/MeOH 19/1, 9/1) to afford 60 mg (56%) of N-(4-chlorobenzyl)-1-methyl-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (DMSO-d6) δ 8.85, 8.44, 7.42-7.33, 6.82, 4.55, 3.92; IR (diffuse reflectance) 3044, 2350, 2318, 1941, 1908, 1679, 1645, 1627, 1553, 1524, 1504, 1466, 803, 672, 656, cm−1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)=O.O1[CH2:32][CH2:31][O:30][CH2:29]C1>[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:29][O:30][C:31]1[CH:32]=[CH:4][C:3]([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:2][CH:7]=1
Reactant: C1COCCO1
Reactant: Nc1cc(Br)cc2nc(-c3ccccn3)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=CO
Product: COc1ccc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)cc1
Temperature: 100 °C
Yield: 17 %

Procedure:
A mixture of 72.5 mg (0.25 mmol) 7-bromo-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 37.4 mg (0.275 mmol) p-methoxy-boronic acid, and 0.22 ml 2M Na2CO3 in 0.78 ml dioxane was treated with 0.05 eq. dichloro (1,1′-bis(diphenylphosphino) ferrocene)palladium (II) dichloromethane adduct and heated to 100° C. for 15 h. Formic acid was added and the mixture was purified by reversed phase column chromatography eluting with an acetonitrile/water gradient yielding 13.3 mg (17%) of the title compound. MS m/e (%): 318 (M+H+, 100)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH:9]=[C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=O)=O.[CH:34]#[C:35][CH2:36][CH2:37][CH3:38]>C(NCC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[C:13]2[CH:12]=[CH:11][C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[CH:9][C:8]=2[C:7]([C:34]#[C:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution (flushed with argon) of 201.3 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 286.5 mg (4.21 mmol) of 1-pentyne, 59.5 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and 32.0 mg (0.17 mmol) of cuprous iodide in 2.5 ml of diethylamine was heated to 70° C. in a pressure vial for 6 hours. After stirring overnight at room temperature, the mixture was diluted with EtOAc (25 ml) and washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% Et2O-hexanes) to give the title compound as a colorless, air-sensitive oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH3:25])[CH:16]=2)=[N:11][CH:12]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH3:25])[CH:16]=3)=[N:11][CH:12]=2)=[CH:29][CH:28]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Cc1cc(C#Cc2ccc(Br)cn2)ccc1OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
40 mL of 2 N aqueous sodium bicarbonate solution was added to a suspension of 13.20 g (39.74 mmol) of 2-[4-(5-bromopyridin-2-ylethynyl)-2-methylphenoxy]ethanol, 9.32 g (59.60 mmol) of 4-chlorophenylboric acid, and 2.30 g (1.99 mmol) of tetrakis(triphenylphosphane)palladium in 400 mL of 1,4-dioxane and the mixture was refluxed for 12 hours. Another 4.66 g of 4-chlorophenylboric acid and 1.14 g of tetrakis(triphenylphosphane)palladium were added and the mixture was refluxed for 8 hours. The reaction mixture was evaporated down in vacuo and the residue was stirred with EtOAc and water. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo. Yield: 10.70 g (74% of theoretical); C22H18ClNO2 (M=363.837); calc.: molpeak (M+H)+: 364/366 (Cl); found: molpeak (M+H)+: 364/366 (Cl); Rf value: 0.47 (silica gel, DCM/EtOAc 2:1).
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:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[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:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cc(F)cc(F)c2)c1
Yield: 52.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3,5-difluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 3,5-difluorophenylboronic acid (0.038 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.051 g (52%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16](Br)[N:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>O1CCCC1>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=3)[N:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1cc2cccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2nc(N)cc3cccnc23)c1
Temperature: 80 °C

Procedure:
To a mixture of tetrahydrofuran (THF) (80 ml) and 2 N sodium carbonate (34 ml, aqueous) is added 6-amino-8-bromo-1,7-naphthyridine (4.007 g), triphenylphosphine (0.37 g) and 3-cyanophenylboronic acid (323 g). The mixture is degassed under argon three times and then bis(dibenzylideneacetone)palladium (0) (0.4 g) is added and the mixture is degassed under argon three more times. The mixture is heated at 80° C. under argon for 16 hours then cooled and filtered. The mixture is diluted with ethyl acetate and washed with 2 N sodium hydroxide then brine. After drying over sodium sulfate the organic layer is evaporated and suspended in ether. The solid precipitate thus obtained is the title compound, which is filtered off. M.p. 182-184° C. HRMS [M+H]+ found=247.1.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[CH:27])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[C:20]3[C:19]([CH3:21])([CH3:22])[CH2:18][CH2:17][C:16]([CH3:23])([CH3:24])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[C:27][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CC(O)c1cc(OCc2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1ccc(COc2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 71 %

Procedure:
In a manner similar to that of Example 1g, by reacting 760 mg (1.9 mmol) of 1-[4-(4-tert-butylbenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 390 mg (1.6 mmol) of 4-iodobenzoic acid in the presence of 15 mg of copper iodide and 28 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=600 mg; yield=71%; m.p.=254° C.).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:39])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: CN(C)CCCCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N1,N1-Dimethyl-hexane-1,6-diamine by the procedure analogous to Example 6. HPLC ret. time: 3.4 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.03 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.19 (t, 2H, J=7.2 Hz), 2.28 (m, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 1.55-1.45 (m, 4H), 1.35-1 .33 (m, 4H) ppm; MS (APCl, m/z): 470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]=CN(C)C)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:22]([C:16]2[C:15]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:35]([F:37])([F:38])[F:36])[CH:4]=3)(=[O:10])=[O:9])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=2)=[O:23])[CH:29]=[CH:28][N:27]=1
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cnc(C(=O)c2ccnc(N)c2)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (23 mg, mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH—CH2Cl2) to afford N-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoro methyl-benzenesulfonamide (12 mg) in 63% yield. 1H NMR (400 MHz, CDCl3) δ 10.75 (s, 1 H), 8.24 (s, 1 H), 8.18 (m, 1 H), 8.07 (dd, 1 H), 7.95 (d, 1 H), 7.75 (d, 1 H), 7.63 (d, 1 H), 7.15 (s, 1 H), 6.95 (d, 1 H), 2.25 (s, 3H); ESMS m/z (relative intensity): 471.0 (M+H)+ (100).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:18]=1[C:19]#[N:20]>>[NH2:16][C:17]1[C:18]([C:19]#[N:20])=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from N-Boc-4-piperidinemethanol and 2-amino-6-fluorobenzonitrile as an off-white solid (37%). 1H NR (400 MHz, DMSO-d6) δ 1.15-1.21 (m, 2H), 1.40 (s, 9H), 1.74 (m, 2H), 1.99 (brs, 1H), 2.74 (brs, 2H), 3.87 (d, J=4.0 Hz, 2H), 3.96 (m, 2H), 5.99 (s, 2H), 6.21 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H). MS 232 (MH+-Boc).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[CH3:42]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:36]4[CH:37]=[CH:38][N:33]=[C:34]([CH3:42])[CH:35]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2cccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 188 step 4) and 2-picoline-4-boronic acid. Off-white solid (60%). MS (EI): 543.2 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:9][C:10]([O:12]CC)=O)(=O)[CH:5]([CH3:7])[CH3:6]>C(O)C>[CH:5]([C:4]1[CH2:9][C:10](=[O:12])[NH:2][N:3]=1)([CH3:7])[CH3:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)C1=NNC(=O)C1
Temperature: 22.5 °C
Yield: 66.5 %

Procedure:
70 g (1.26 mol) of hydrazine hydrate were added dropwise at 10 to 30° C. to a solution of 100 g (0.62 mol) of ethyl isobutyrylacetate in 60 ml of ethanol. After the exothermic reaction had subsided, the mixture was stirred at 20 to 25° C. for a further 14 hours approximately and was then cooled to approximately −10° C. 52 g of the title compound were isolated by filtration.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.Br[CH2:16][CH2:17]Br>CS(C)=O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:16]2)[N:4]=1
Reactant: CCOC(=O)Cc1cccnn1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 830 mg, 21.66 mmol) was washed with petroleum ether under a nitrogen atmosphere to remove the mineral oil. Dimethylsulfoxide (10 mL) was added and the resulting suspension was stirred for 5 min before adding ethyl 2-(pyridazin-3-yl)acetate (600 mg, 3.61 mmol) and 1,2-dibromoethane (2.03 g, 10.83 mmol) dissolved in dimethylsulfoxide (10 mL) at 10° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified via column chromatography (100-200 silica gel mesh, 50-60% ethyl acetate in petroleum ether) to afford ethyl 1-(pyridazin-3-yl)cyclopropanecarboxylate (300 mg). MS (ES+APCI) (M+H) 193.0.