Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].C1COCC1.O.[OH-].[Li+]>CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN(C)CCCN
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N,N-dimethyl-1,3-propanediamine (available from Aldrich Chemical Company, Inc.; 42 mg, 0.41 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. Lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight, and then another portion of lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-dimethylamino-propylcarbamoyl)-biphenyl-2-carboxylic acid (102 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 8.68 (t, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 3.34-3.40 (m, 2H), 3.08-3.16 (m, 2H), 2.79-2.82 (m, 6H), 1.86-1.95 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N:36]([CH3:37])[CH3:38])=[CH:34][CH:35]=2)[CH2:26][CH3:27])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCc1ccc(N(C)C)cc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1ccc(N(C)C)cc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with (4-ethylaminomethyl-phenyl)-dimethyl-amine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(S(C)(=O)=O)CC3)cc3c(Br)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of Example 5E (6.5 g, 12.73 mmol) in 1,4-dioxane (50 mL) was added a solution of sodium hydroxide (1.528 g, 38.2 mmol) in water (5 mL) and the mixture was stirred at 60° C. for 12 hours. The mixture was concentrated and the residue was suspended in water and N,N-dimethylformamide. The suspension was filtered and the solid was washed with ethyl acetate to provide the title compound. MS (CI) m/z 356 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[C:8](N)[CH:9]=[CH:10][C:2]1=2.[NH2:12]C1C=CC([N+]([O-])=O)=CC=1O>>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][C:2]1=2
Reactant: Nc1ccc2c(c1)NCCO2
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: Nc1ccc2c(c1)OCCN2

Procedure:
The above was prepared using the same procedure as for 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, except 2-amino-5-nitrophenol was used as starting material.
Reaction SMILES: Cl[C:2]1C(Cl)=CC(C(Cl)(Cl)Cl)=C[N:3]=1.Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.[C-]#N.[K+]>CS(C)=O>[Cl:20][C:19]1[C:14]([C:2]#[N:3])=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-Chloro-2-fluoro-5-(trifluoromethyl)pyridine (obtained as a by-product from the fluorine exchange reaction when converting 2,3-dichloro-5-trichloromethyl pyridine to 2,3-dichloro-5-(trifluoromethyl)pyridine) (40.0 g, 0.2 mole) was put into 270 ml of dimethyl sulfoxide and stirred while potassium cyanide (14.4 g, 0.221 mole) was spooned in over a 20-minute period. The mixture was then stirred for another 20 minutes. The temperature was held between 23° and 28° C. throughout the reaction. The mixture was poured into 600 ml of ice water and the product was extracted into hexane. The hexane was removed on a rotary evaporator. The product was treated with activated charcoal and distilled on a Vigreaux-Claisen still at 108°-110° C. at 30 mm Hg to yield 31.45 g of colorless oil with an analysis of, in percent by weight:
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:51]([O:53][CH3:54])[CH3:52])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:51]([O:53][CH3:54])[CH3:52])[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3]
Reactant: COC(=O)c1c(C(C)(C)O)nc(C(C)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C(C)(C)O)nc(C(C)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 83.2 %

Procedure:
A solution of 600 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-(1-methoxyethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 1.5 hours. The solution was then mixed with 10 ml of water and cooled with ice. The trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with toluene, to give 331 mg of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>ClCCl.O>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)C(C)C)COC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added diisopropylethylamine (50 mg, 0.390 mmol) and isobutyryl chloride (41 mg, 0.391 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:24]([NH:26][NH2:27])=O>>[F:20][C:21]1[CH:22]=[C:23]([C:24]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[N:27][N:26]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1cc(F)cc(F)c1
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cc(F)cc(F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 3,5-difluorobenzohydrazide: MS (ES) m/z 405 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:17]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[C:33]([O:37][C:38]([N:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:41][C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:33]([O:37][C:38]([N:40]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:41][C:42]([N:30]1[CH2:29][CH2:28][N:27]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:32][CH2:31]1)=[O:43])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCCCCCCCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCN1CCN(C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
2.3 g (8.64 mmole) quantity of N,N'-dicyclohexylcarbodiimide was added to 20 ml of a solution of 2.0 g (7.35 mmole) of N-decylpiperazine hydrochloride, 1.9 g (7.56 mmole) of N-t-butoxycarbonylphenylglycine, 1.3 g (15.5 mmole) of sodium hydrogencarbonate and 122 mg (1.0 mmole) of 4-dimethylaminopyridine in anhydrous methylene chloride. The mixture was stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with methylene chloride. Mother liquor and the washings were combined and concentrated under reduced pressure and the residue was purified by silica gel chromatography (chloroform : methanol =15 : 1), giving 2.8 g (yield: 83 %) of 1-(N-t-butoxycarbonyl-phenylglycyl)-4-decylpiperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1 ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling dry nitrogen through it for 15 minutes, and 0.7 g (0.00I mol) of bis(triphenyl-phosphine)palladium dichloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of a gold oil. The oil was triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1)#[N:2].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(C(C)=O)C>[C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)#[N:2]
Reactant: ClCc1ccccc1
Reactant: N#CCCC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCC1CN(Cc2ccccc2)CCO1
Yield: 90.2 %

Procedure:
A mixture of 2-(2-cyanoethyl)morpholine (5.4 g), benzyl chloride (5.4 g), potassium carbonate (5.4 g), potassium iodide (0.5 g), and methyl ethyl ketone (30 ml) is heated under reflux for 1 hour. After cooling, the reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in diethyl ether, and the solution is extracted with dilute hydrochloric acid. The extracts are basified with dilute aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to give the title compound (8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)CC)C.[C:51](Cl)(Cl)=[O:52].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[N:4]1[CH2:5][C:6]2[C:7](=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][Si:23]([C:36]([CH3:37])([CH3:38])[CH3:39])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:16]=2)[C:51]1=[O:52]
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2ccccc2Br)c(Nc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(c1cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(=O)N(c1ccccc1Br)C2
Yield: 100 %

Procedure:
A solution of 4.5 g (6.8 mmol) 5-((2-bromoanilino)methyl)-4-[3-(tert-butyldiphenylsilyloxymethyl)anilino]-2-methylthiopyrimidine and 1.9 ml (13.6 mmol) of triethylamine in 50 ml of toluene was added dropwise to a solution of 7 ml of a 20% solution of phosgene in toluene (13.6 mmol) in a further 50 ml of toluene. The mixture was heated at reflux for 5 hours and the cooled. 50 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate were added and the mixture separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 4.7 g (100%) of 3-(2-bromophenyl)-1-[3-(tert-butyldiphenylsilyloxymethyl)phenyl]-3,4-dihydro-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one as a colorless oil. [Mass spectrum (ESI) MH+ =696].
Reaction SMILES: Br[C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33](C=O)C.CCOC(C)=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:32]([C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:33]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)c1ccc2cccnc2c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1[C@@H](NC(=O)c1ccc2cccnc2c1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a microwave vial were added (S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide (Example 195) (0.100 g, 0.206 mmol), zinc cyanide (0.026 mL, 0.411 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.024 g, 0.021 mmol), and DMF (1.3 mL). The resulting mixture was then subjected to microwave irradiation at 130° C. for 30 min. EtOAc (10 mL) and H2O (10 mL) were then added, and the resulting mixture was stirred at rt for 5 min. The organic layer was collected, dried over MgSO4 and concentrated. The residue was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1 mL). The solution was washed through PL_HCO3 MP-SPE resin and the resin was washed with MeOH (2×1 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, MeOH) δ ppm 8.98 (dd, J=4.1, 1.6 Hz, 1H), 8.93 (dd, J=4.9, 1.6 Hz, 1H), 8.60 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.25 (dd, J=7.8, 1.6 Hz, 1H), 8.08 (s, 2H), 7.70-7.81 (m, 4H), 7.66 (dd, J=8.4, 4.3 Hz, 1H), 7.58 (dd, J=7.8, 4.9 Hz, 1H), 6.91 (s, 1H). MS (ESI pos. ion) m/z: 433.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[CH3:28][N:29]([CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:30][CH2:31][OH:32]
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)CCO

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol as light brown oil, MS: 391 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[Si:19]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNCCO[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a stirred solution of 2-methylamino-ethanol (18-a) (10 g, 133.13 mmol) in dichloromethane (200 mL) were added diisopropylethylamine (30.8 ml, 186.39 mmol) and tert-butyl-chloro-dimethyl-silane (20.06 g, 133.13 mmol) at room temperature. The mixture was stirred for 16 h. After completion of the reaction, water was added and the mixture was extracted with dichloromethane. The separated organic part was washed with water and was dried over sodium sulfate and concentrated under reduced pressure to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) (18 g, 71.39%) as a yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[N:23]([CH3:28])[N:24]=[CH:25][C:26]=3[Br:27])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31].Cl>C(O)C>[Br:27][C:26]1[CH:25]=[N:24][N:23]([CH3:28])[C:22]=1[C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:30][OH:31])[CH3:2])[CH:5]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=NO)c2)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Compound 17 (54 mg, 0.12 mmol, see Example 1.24) was dissolved in ethanol (10 mL). Hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added under Argon gas. The pH of the solution was then adjusted to pH=4 with 1N Hydrogen Chloride solution. The reaction was stirred overnight at room temperature and found to be complete by TLC and LC/MS. The ethanol was removed under reduced pressure. Then, the residue was worked up with EtOAc (2×20 mL) and Brine (20 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 8.8 mg (16%) of Compound 96: LCMS m/z (%)=458 (M+H79Br, 96), 460 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.48 (dd, J1=12 Hz, J2=4 Hz, 1H), 7.42 (s, 1H), 7.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.39 (d, J=4 Hz, 1H), 7.30 (t, 1H), 7.19 (d, J=8 Hz, 1H), 7.15 (s, 1H), 7.08 (dd, J1=12 Hz, J2=4 Hz, 1H), 6.88 (dd, J1=12 Hz, J2=8 Hz, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>O1CCCC1.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>[Br:20][C:21]1[N:22]=[C:23]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccncc2)n1
Yield: 53.8 %

Procedure:
4-Tri-n-butylstannylpyridine (3.30 g, 8.9 mmol) was added to a degassed and stirred solution of 2,6-dibromopyridine (2.00 g, 8.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mol %) in tetrahydrofuran (30 ml) under an atmosphere of nitrogen then heated to reflux for 48 h. Solvent was removed in vacuo and purification by chromatography on silica gel eluting with dichloromethane followed by trituration with isohexane gave 6-bromo-2,4′-bipyridinyl (1.05 g) as a white solid: δH (400 MHz, CDCl3) 7.52-7.57 (1H, m), 7.66-7.70 (1H, m), 7.86 (2H, m), 8.10-8.50 (1H, m), 8.72-8.76 (1H, m), 8.77-8.81 (1H, m); m/z (ES+) 234/236 (M++H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][N:16]3[N:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][N:16]3[N:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cc(Cn3ncc([N+](=O)[O-])n3)ccn2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cc(Cn3ncc(N)n3)ccn2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(2-methyl-[1,3]dioxolan-2-yl)-4-(4-nitro-[1,2,3]triazol-2-ylmethyl)-pyridine (145 mg, 0.50 mmol), iron powder (84 mg, 1.49 mmol) and NH4Cl (134 mg, 2.49 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a light yellow oil. LC-MS-conditions 02: tR=0.54 min; [M+H]+=261.78.