Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=O)=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[CH2:1])=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butyl lithium (1.6M, 6.2 mL, 9.92 mmol) was added dropwise to a THF (20 mL) solution containing methyltriphenylphosphonium bromide (3.65 g, 10.22 mmol) cooled in an ice bath. The solution was stirred at room temperature for 3 hours. A THF (5 mL) solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one (1 g, 5.68 mmol) was added dropwise. The solution was then stirred at 60° C. overnight. The solution was partitioned between ethyl ether and water. The organic phase was washed with water (3×) and brine and dried over MgSO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J=2.6 Hz, 1H); 7.10 (d, J=8.3 Hz, 1H); 6.86 (dd, J=2.6, 8.4 Hz, 1H); 5.55 (s, 1H); 5.05 (s, 1H); 3.88 (s, 3H); 2.86 (t, J=6.3 Hz, 2H); 2.61 (t, J=6.2 Hz, 2H); 1.96-1.92 (m, 2H). LCMS1 3.79 min. (M+1)=175
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]=[N+:23]=[N-:24])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(N)ccc1Nc1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(N=[N+]=[N-])ccc1Nc1ccccc1

Procedure:
The same procedures as in Example A were repeated except that 10 parts of 2-phenylamino-5-aminobenzoic methyl ester were used as the starting compound, and the aqueous solution of 10% sodium nitrite and the aqueous solution of 10% sodium azide were used in amount of 28 parts and 33.2 parts, respectively, 2-phenylamino-5-azidobenzoic methyl ester having a melting point of 64° to 65° C was obtained at an amount of 9.5 parts.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C.C(O)C>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1

Procedure:
A solution of 37.9 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine-N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml triethylamine is stirred under nitrogen at reflux for 21/2 hours. Dark solution is cooled in an ice bath, then 40 ml of ethanol added followed by 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (1:10) to yield 4-(tert-butyl-dimethylsilyloxymethyl)-2-cyanopyridine.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([F:16])[F:15])[CH3:11]>[Cu].CS(C)=O>[CH2:10]([O:12][C:13](=[O:18])[C:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([F:16])[F:15])[CH3:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (K. Sato et al., Chem. Pharm. Bull., vol. 47 p. 1013 (1999)) and the above-described scheme, 4-iodobenzonitrile (Compound 1a; 343.5 mg, 1.5 mmol), bromodifluoroacetic acid ethyl ester (304.5 mg, 1.5 mmol), copper powder (190.5 mg, 3.0 mmol) and DMSO (3.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2a) was obtained with a yield of 60%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH2:39])[CH:38]=1)(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:38]=1)(=[O:32])=[O:33]
Reactant: Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedure II.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.C([O-])(O)=O.[Na+].C(O)(C)C.C(Cl)Cl>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:13]1[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3ccccc3n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(C3CNC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(quinolin-2-yl)azetidine-1-carboxylate (2.8 g, 9.8 mmol, as prepared above) in DCM (10 mL), TFA (10 mL) was added. The resulting mixture was stirred at rt for 2 h and concentrated to obtain a viscous oil which was dried under reduced pressure. The residue obtained was dissolved in DCM (50 mL) and stirred with saturated NaHCO3 (50 mL). The DCM layer was separated and the aqueous layer was concentrated. To the residue obtained, 20% iso-PrOH/DCM (50 mL) was added and stirred for 10 min and filtered. This procedure was repeated three times. The combined filtrates were dried over Na2SO4, filtered, and concentrated to obtain compound 24d as a gummy solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.34 (d, J=8.6 Hz, 1H), 7.94-8.01 (m, 2H), 7.76 (s, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 3.89-4.30 (m, 4H), 3.72-3.82 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)CCC>[O:8]([C:7]1[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ncccc1Oc1ccccc1
Reactant: C1CNCCN1
Solvent: CCCCO
Product: c1ccc(Oc2cccnc2N2CCNCC2)cc1

Procedure:
To a solution of 10.5 g of 2-chloro-3-phenoxypyridine in 25 ml of n-butanol is added 20 g of piperazine and the solution is refluxed for 24 hours. The resulting mixture is concentrated at reduced pressure. The residue is shaken with 500 ml of ether and excess dilute aqueous sodium hydroxide. The organic phase is separated, dried and filtered. The filtrate is concentrated and the product distilled to give 3-phenoxy-2-piperazinylpyridine; bp, 115°-117° C./0.15 mm, crystallized and has a mp 56°-59° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](C)([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Na+].[Cl-]>CS(C)=O.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)c1ccc(Cl)nn1
Temperature: 175 °C
Yield: 35.2 %

Procedure:
A solution of diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate (11 g, 38.4 mmol) and NaCl (2.69 g, 46.0 mmol) in DMSO (91 mL) and H2O (1.382 ml) was divided into eight separate microwave vials and each reaction was heated in a microwave at 175° C. for 90 mins on high absorbance. The reactions were combined and then poured into H2O (300 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and then the organic phase was washed with brine (2×100 mL). The organic phase was dried over MgSO4, filtered and concentrated to dryness via rotary evaporation. The resulting oil was purified via MPLC (3:1, Hex:EtOAc) to provide the title compound, ethyl 2-(6-chloropyridazin-3-yl)propanoate (54A, 2.9 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 3 H) 1.49 (d, J=7.33 Hz, 3 H) 4.09 (dd, J=7.07, 2.02 Hz, 2 H) 4.23 (d, J=7.33 Hz, 1 H) 7.83 (d, J=8.84 Hz, 1 H) 7.93 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 215.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(N)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (2.6 g, 8.26 mmol) in dichloromethane (50 mL) was added triethylamine (918 mg, 9.09 mmol) and DMAP (20 mg) followed by dropwise addition of benzoyl chloride (1.27 g, 9.1 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and sat. aqueous NH4Cl. The organic layer was washed with water (30 ml), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (10-25% ethyl acetate/petrol ether) to afford the title compound as a colourless oil (2.07 g, 60%); 1H NMR (400 MHz, CDCl3) δ 1.48 (9H, s), 3.35 (1H, dd), 3.55 (1H, dd), 5.5 (1H, m), 6.26 (1H, t), 6.90 (1H, d), 7.15 (2H, m), 7.28 (3H, m), 7.52 (3H, m), 7.95 (2H, m), 8.52 (1H, d), 9.22 (1H, br s).
Reaction SMILES: CC1N2N=NN=C2C2N=C(CCC)N(CCCS(C3C=CC(C(Cl)=O)=CC=3)(=O)=O)C=2C=1C.C(N)CCC.N1CCOCC1.[CH2:44]([NH:48][C:49](=[O:79])[C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH2:59][CH2:60][CH2:61][N:62]2[C:70]3[C:69]([CH3:71])=[C:68]([CH3:72])[N:67]4N=N[N:75]=[C:66]4[C:65]=3[N:64]=[C:63]2[CH2:76][CH2:77][CH3:78])(=[O:58])=[O:57])=[CH:52][CH:51]=1)[CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:75][C:66]1[C:65]2[N:64]=[C:63]([CH2:76][CH2:77][CH3:78])[N:62]([CH2:61][CH2:60][CH2:59][S:56]([C:53]3[CH:54]=[CH:55][C:50]([C:49]([NH:48][CH2:44][CH2:45][CH2:46][CH3:47])=[O:79])=[CH:51][CH:52]=3)(=[O:58])=[O:57])[C:70]=2[C:69]([CH3:71])=[C:68]([CH3:72])[N:67]=1
Reactant: CCCCNC(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c2c(C)c(C)n2nnnc32)cc1
Agent: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1COCCN1
Solvent: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c(N)nc(C)c(C)c32)cc1
Reaction time: 8 h

Procedure:
The general methods described in Example 101 were followed with the following modifications. To one-third of the crude solution of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoyl chloride in dichloromethane, described in Part B of Example 101, was added butylamine (0.49 mL, 4.9 mmol) in lieu of morpholine, and the reaction was stirred overnight. Additional butylamine (0.5 mL) was added, and the reaction was stirred for two hours. Dichloromethane (100 mL) was added to the reaction mixture, and the resulting solution was washed with saturated aqueous sodium carbonate (3×25 mL), water (3×25 mL), 10% by volume acetic acid in water (3×30 mL), and water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dried for three hours in a vacuum oven at 100° C. and then triturated with ethyl acetate to provide a solid that was isolated by filtration and dried for three hours in a vacuum oven at 90° C. N-Butyl-4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzamide (830 mg, 1.62 mmol) was treated as described in Part C of Example 101. The crude product was purified by column chromatography on silica gel (eluting sequentially with chloroform and 90:10 chloroform:methanol) to provide the product as an oil, which was recrystallized from ethyl acetate:hexane with a few drops of methanol to yield crystals. The crystals were isolated by filtration, washed with hexanes, and dried in a vacuum oven at 80° C. to provide 0.18 g of 4-[3-(4-amino-6,7-dimethyl-2-propyl-1II-imidazo[4,5-c]pyridin-1-yl)propane-1-sulfonyl]-N-butylbenzamide as a white powder, mp 147.0–149.0° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[O:13])[S:10][CH:11]=2)=[C:5]([CH3:36])[N:4]=[N:3]1.C1C(=O)N([Cl:44])C(=O)C1.CCOC(C)=O>CN(C)C=O>[Cl:44][C:11]1[S:10][C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[O:13])=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][C:5]=1[CH3:36]
Reactant: Cc1nnn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Yield: 31.1 %

Procedure:
A solution of 4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (254 mg, 0.454 mmol), and NCS (60.6 mg, 0.454 mmol) in N,N-Dimethylformamide (DMF) (5 mL) to was heated at 40° C. overnight. The reaction mixture was taken into EtOAc, which was washed with H2O 3× and brine, dried (Na2SO4) and concentrated. The residue was purified on a 25 g Biotage column, which was eluted with 50-100% EtOAc/hexane to give 76 mg (28%) of product as a white foamy solid and 63 mg of recovered starting material. LC-MS (ES) m/z 538.0 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].[OH-].[Na+]>Cl.O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]2[NH:15][C:2]([CH2:1][OH:5])=[N:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(O)CO
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]c(CO)nc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6.2 g (81.5 mmol) glycolic acid is added to a solution of 6.24 g (40.8 mmol) 4-nitro-o-phenylenediamine in 80 mL semiconcentrated HCl. The reaction solution is refluxed for 4 h and the solvent is eliminated i.vac. The residue is taken up in water and made basic with 2 N NaOH. The product precipitates out and is stirred for another 1 hour in the ice bath. The precipitate is suction filtered and washed successively with water and PE. The product is dried at 40° C. This still contains 40% 4-nitro-o-phenylenediamine. It is again taken up in semiconcentrated HCl and after the addition of 6.5 mL glycolic acid (57% in water) it is refluxed for 3 h and heated for a further 12 h at 80° C. The solvent is eliminated i.vac. and the residue is dissolved in water and made alkaline with 6 N NaOH, during which time the product is precipitated. The precipitate is suction filtered and washed successively with water and PE. The product is dried in the circulating air dryer at 50° C.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:28](/[CH:29]=[CH:30]/[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])#[N:31]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reactant: C=CC#N
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C=C/C#N)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reaction time: 2 h

Procedure:
A mixture of 0.5 mmol 4-[4-(2-Iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (Example AG), 6.3 mmol acrylonitrile, 9.0 mmol triethylamine and 0.2 mmol of bis-(triphenylphosphin)-palladium(II)-dichloride in 10 ml dimethylformamide is hold under argon for 2 hours at 80°. The reaction mixture is concentrated. Chromatography (SiO2; cyclohexane/ethyl acetate 9:1) yields the title compound as a slightly yellow solid (105 mg). ). (M+H+: 421.2)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(=S)=S.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 28.9 %

Procedure:
Aluminum chloride (26.0 g, 195 mmol) was added in portions to a solution of 4-nitrobenzoyl chloride (27.8 g, 150 mL) and 4-fluorobenzene (15.8 g, 165 mmol) in carbon disulfide (100 mL). After 1 hour, the resulting yellow mixture was carefully treated with concentrated hydrochloric acid (60 mL) and stirred for 30 minutes. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, water and brine, dried (MgSO4), and the solvent removed in vacuo. Crystallization from ethyl ether/hexanes gave 4-(4-fluorobenzoyl)-nitrobenzene (10.6 g, 82%) as a white solid, m.p. 87-88° C.; Analysis for C13H8NO3F: Calc.: C, 63.69; H, 3.26; N, 5.74: Found: C, 63.89; H, 3.28; N, 5.78.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:31]=1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[CH3:51])=O.[NH4+].[Cl-]>C1COCC1>[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:31]=1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[CH3:51])=[CH:2][O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ccc1C(=O)c1c(-c2ccccn2)nn(C)c1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC=C(c1ccc(Cl)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (91 g, 265 mmol) in THF (330 mL) at about −10° C. was added 1.6 M butyllithium in hexanes (161 mL, 258 mmol) dropwise. The mixture was stirred at about −10° C. for about 1 h. A solution of (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanone (22.35 g, 64.6 mmol) in THF (220 mL) was added to the mixture in a dropwise manner. The mixture was stirred at about −10° C. for about 16 h then treated with a saturated aqueous NH4Cl solution (1000 mL). The mixture was extracted with EtOAc (2×700 mL). The combined organic layers were washed with brine (500 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-25% EtOAc/heptanes) to give 2-(5-chloro-4-(1-(4-chloro-2-methylphenyl)-2-methoxyvinyl)-1-methyl-1H-pyrazol-3-yl)pyridine (16.65 g, 69%): LC-MS (Table 1, Method g) Rt=2.56 min, m/z 374/376 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 8.44-8.39 (m, 1H), 7.70-7.58 (m, 2H), 7.21-6.93 (m, 4H), 6.39 (s, 1H), 3.90 (s, 3H), 3.64 (s, 3H), 2.28 (2s, 3H) major; 1H-NMR (CDCl3, Bruker 400 MHz) δ 8.44-8.39 (m, 1H), 7.70-7.58 (m, 2H), 7.21-6.93 (m, 4H), 6.38 (s, 1H), 3.88 (s, 3H), 3.52 (s, 3H), 2.20 (s, 3H) minor.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:12])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3N3CCOCC3)CC2)s1
Yield: 60 %

Procedure:
Prepared in analogy to example 1 (b) from 5-Methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A13) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 60%). MS (m/e): 557.2 (M+H+, 65%), 574.4 (M+NH4+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(OC([NH:43][CH2:44][C:45](O)=[O:46])=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH2:43][CH2:44][C:45]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1)=[O:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCC(=O)N1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.026 g, 0.05 mmol) and tert-butoxycarbonylamino-acetic acid (0.0087 g, 0.05 mmol) in dichloromethane (3 mL) was treated with EDCI (0.0104 g, 0.055 mmol) and triethylamine (0.006 g, 0.06 mmol). Reaction mixture was stirred at room temperature for 18 hours and was then partitioned between dichloromethane and an aqueous saturated hydrogenocarbonate solution. The dichloromethane layer was then washed with aqueous 10% citric acid, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (26 mg, 77%).