Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH:3]([C:6]1[S:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)([CH3:5])[CH3:4]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:1])=[O:12])[CH:10]=1)([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)c1cc(C=O)cs1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)c1cc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of AgNO3 (1.01 g, 5.92 mmol)in 10 mL of H20 and 15 mL of a solution of KOH (1.63 g, 40.8 mmol) were sequentially added to a solution of 760 mg (4.9 mmol) of 2-isopropyl-4-thiophene carboxaldehyde, from step 34a above, in 25 mL of ethanol. The resulting black mixture was stirred at room temperature for 2 hours and filtered. The filtrate was washed with ether, then acidified with 6N HCl and extracted with ether. The extract was washed with H2O and brine, dried over MgSO4 and concentrated to give 680 mg (81%) of the title compound as a yellow solid. mp. 64°-67° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Yield: 89 %

Procedure:
A mixture of 5-bromo-3-nitropyridin-2(1H)-one (Step A, 2.5 g, 10.4 mmol), phosphoryl chloride (25 mL) and N,N-dimethylformamide (2.5 mL) was stirred under reflux for 3 h. After removal of solvent, the residue was dissolved in water (20 mL) and diethylether (20 mL) at 0° C. and the solution was separated. The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (2.5 g, 89%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.N>Cl.CCO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1
Yield: 119.7 %

Procedure:
To a solution of stannous chloride dihydrate (32.38 g, 0.14 mol) in concentrated HCl (11 mL) was added 3,5-dichloro-4-(4-methoxy-phenoxy)nitrobenzene (11.3 g, 0.03 mol) in EtOH (56.5 mL). The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30° C. and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give 3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g; % Yield: 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:20][CH2:21][CH2:22][C:23](O)=[O:24])[C:17]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:16]([NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:49]([C:52]1[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=1[NH2:54])([CH3:51])[CH3:50]>>[CH:49]([C:52]1[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=1[NH:54][C:23](=[O:24])[CH2:22][CH2:21][O:20][C:18]1[C:17]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:16]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]([CH3:48])([CH3:46])[CH3:47])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[N:19]=1)([CH3:51])[CH3:50]
Reactant: CC(C)c1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[2-(4-t-butoxycarbonylpiperazinyl)-6-(4-t-butyl-phenylsulfonylamino)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]-propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](Cl)=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:37][CH:36]=3)=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)Cl)cc1
Reactant: Br[Mg]c1ccc(OCCN2CCCCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid chloride (98.5 mg, 0.296 mmol) in tetrahydrofuran (3 ml) at 2° C. under nitrogen is added dropwise via syringe a solution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (0.48 ml of 0.75 M solution, 0.36 mmol). The resulting mixture is stirred at that temperature for 16 hours, then quenched by addition of methyl alcohol. It is then partitioned between methylene chloride and saturated aqueous ammonium chloride, and the separated organic layer is dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica gel (10:5:1 hexanes:dichloromethane:triethylamine) to afford a product-containing fraction, which is further chromatographed on silica gel (10:1:1 hexanes:dichloromethane:triethylamine) to afford title compound as an oil: 88.4 mg (60%). 1H NMR spectrum identical to authentic sample. Anal. Calcd. for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found: C, 71.59; H, 6.32; N, 2.69; S, 6.14.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11](I)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31].Cl>O.O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11]([CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Reactant: CC(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2noc(C)n2)c(C(O)C(C)C)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 3-(4-benzyloxy-2-iodo-5-methoxy-phenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (844 mg) and tetrahydrofuran (6 mL) was cooled in an ice salt bath under an argon atmosphere. Isopropylmagnesium chloride (2.0 mol/L tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred under ice-salt-bath cooling for 10 minutes. After an addition of isobutyraldehyde (0.55 mL), the mixture was stirred in an ice salt bath for 10 minutes, and at room temperature for 30 minutes. Water and 2 mol/L hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15%-35% ethyl acetate/hexane, gradient elution) to give the title compound (533 mg).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[NH2:30]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:30][C:24]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[Cl:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(C(=O)NCC3CCCCC3)c(C(F)(F)F)n2)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) was added 2-chloro-4-methylphenylamine (Aldrich) (109 mg) the mixture was stirred at reflux for 24 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit The residue was taken up into methanol (0.5 ml) and dimethylsulfoxide (0.5 ml) and purified using mass directed auto-preparative system to give the title compound) (24 mg)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].CC(C)([O-])C.[K+].Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].O>CS(C)=O>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:5]([C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCN(c1cccc([N+](=O)[O-])c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (23.1 mmol) of 3-methylsulphonylamino-nitrobenzene are dissolved in 50 ml of DMSO and combined with 6.5 g (58 mmol) of potassium tert. butoxide while cooling with ice. The solution thus obtained is added dropwise to a solution of 5 g (34.7 mmol) of 2-chloro-N,N-dimethyl-ethylamine in 30 ml of DMSO. The mixture is stirred for 2 hours at ambient temperature and then heated for 6 hours to 100° C. After cooling to ambient temperature 400 ml of water are added. The mixture is extracted with ethyl acetate. Water and 1 N hydrochloric acid are added to the combined organic phases until an acid reaction is obtained. The aqueous phase is washed with ethyl acetate. Then the aqueous phase is made alkaline with sodium carbonate and the product is extracted with ethyl acetate. Drying the combined organic phases over magnesium sulphate and eliminating the solvents in vacuo yields the product as a red oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([C:45]([O:47]C)=O)=[N:25][C:26]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:44]=CC=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.[C:49]1([CH2:55][CH2:56][NH2:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:33]1([CH:32]([C:39]2[CH:8]=[CH:9][CH:5]=[CH:6][CH:44]=2)[CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:45]([NH:57][CH2:56][CH2:55][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:47])[N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=3)[O:7]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCc1ccccc1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)OC)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCc5ccccc5)nc43)[C@H](O)[C@@H]2O)n1
Temperature: 130 °C
Yield: 100.9 %

Procedure:
A mixture of methyl 9-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 30) (100 mg, 0.15 mmol) and 2-phenylethylamine (0.2 ml, 1.58 mmol) were heated together under a nitrogen atmosphere at 130° C. for three hours. The mixture was allowed to cool to room temperature and was then purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate gradually changing to ethyl acetate:methanol (95:5 by volume). Product containing fractions were evaporated and the resulting solid was triturated with ether, filtered and dried to afford the title compound as a white powder (50 mg).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[NH2:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([NH2:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: NC1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-aminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.61 (s, 1H), 4.01 (m, 2H), 3.80 (m, 2H), 3.45 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 439 [M+H]
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>CO>[CH2:1]([CH:8]1[C:9]2([C:28]3[NH:29][C:30]4[C:35]([C:27]=3[CH2:26][CH2:25][NH:24]2)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([N:20]([CH3:22])[CH3:21])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Reactant: NCCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC2(NCCc3c2[nH]c2ccccc32)C(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(±)-2-benzyl-4-dimethylamino-4-phenylcyclohexanone (307 mg, 1 mmol) together with tryptamine (160 mg, 1 mmol) was dissolved in methanol and stirred at RT for 24 h. The solvent was then removed in a vacuum and the residue dissolved in 1,2-dichloroethane (20 ml). The mixture was mixed with trifluoroacetic acid (1.7 ml, 22.8 mmol) and stirred for 24 h at RT. For work up the reaction mixture was mixed with 2N NaOH (20 ml) and stirred for 20 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (4×20 ml). The combined organic phases were dried with MgSO4. The solvent was then concentrated by evaporation in a vacuum. One of the possible diastereoisomers was isolated from the residue obtained (260 mg) by means of chromatographic purification [silica gel 60 G (10 g); ethyl acetate/ethanol 1:1 (80 ml), methanol (60 ml)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][C:22]1[CH:21]=[C:20]([CH:10]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc(N)c2)cc1C
Yield: 94.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer A of N-[(3-nitrophenyl)-(3,4-dimethylphenyl)methyl]-N-[(S)-1-phenylethyl]amine (1.10 g) [prepared as described in step (a) above] in methanol (20 ml), nickel chloride hexahydrate (1.45 g) and sodium borohydride (469 mg) were reacted, to afford isomer A of the title compound (954 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:34][CH:33]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5cccc(S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (245.0 mg, 1.180 mmol) in a manner analogous to Example 2d. Product was isolated as a pale yellow solid (0.268 g, 77%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=6.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.03 (s, 1H), 6.99 (t, J=6.9 Hz, 1H), 3.09 (s, 3H). MS=323, 325 (MH)+. 109b) N(8)-(3-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.261 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 7.59-7.43 (m, 5H), 7.20 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.19-3.14 (m, 4H), 3.07 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:23]=[CH:22][C:11]2[N:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:16])[N:14]([CH3:15])[C:10]=2[CH:9]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O.C1COCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Reactant: OB(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate (3.66 g, 11.2 mmol, 3.0 eq) in Water (1 ml) was charged with a solution of 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5, 1.37 g, 3.74 mmol) dissolved in anhydrous THF (19 ml). 3-Hydroxyphenyl boronic acid was introduced and the solution was deoxygenated. The 1,1′-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (153 mg, 0.19 mmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 125 deg C. for 15 min. LC/MS analysis showed ˜50% conversion, so more of each reagent was added and the reaction was irradiated again at 120 deg C. for 30 min. The completed reaction was partitioned between EtOAc (2×25 ml) and saturated aqueous NaHCO3 (25 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography (SiO2: 100% Hex to 60:40 EtOAc/Hex), affording 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1479) as a pink-orange solid. 1H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.21-7.15 (m, 2H), 7.11-7.06 (m, 2H), 6.81 (d, 1H, J=5.4 Hz), 3.68 (s, 2H), 3.47 (s, 3H), 1.07 (s, 9H). LRMS m/z: Calc'd for C19H22N2O2 (M+H) 311.4, found 311.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[S:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]2[CH:12]([S:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]([C:10]3[S:9][CH:13]=[CH:12][CH:11]=3)[S:9][CH:10]2[C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C1CCSC1
Reactant: Sc1ccc(Cl)cc1
Product: Clc1ccc(SC2C(c3cccs3)SC(c3cccs3)C2Sc2ccc(Cl)cc2)cc1

Procedure:
Starting from 4-chlorothiophenol, the synthesis of this compound is analogous to that of the tetrahydrothiophene synthesized in Example 2.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[Na+]>[CH2:11]([O:10][C:8]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
26.7 g (0.3 mol) of sarcosine were dissolved in 150 m (0.3 mol) of 2-N sodium hydroxide. The resulting solution was stirred at 0° C. while 75 ml of 4-N sodium hydroxide and 51.3 ml (ca 360 mmol) of benzyl chloroformate were added alternately and portionwise over a period of 0.5 hour, the temperature being held below 5° C. The mixture was stirred for a further 1 hour while the temperature was allowed to rise to room temperature. The mixture was then extracted with two 300 ml portions of diethyl ether. The aqueous layer was separated, cooled to 0° C. and, while stirring, made acid to Congo red with ca 25 ml of concentrated hydrochloric acid. The mixture was stirred for 1 hour while allowing the temperature to rise to room temperature. The mixture was then extracted with three 300 ml portions of diethyl ether, the combined extracts were dried over sodium sulphate and evaporated to give ca 64 g of N-benzyloxycarbonyl-sarcosine in the form of an oil.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[CH2:3][C:4]#[N:5]>C1COCC1>[NH2:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[OH:1]
Reactant: N#CCC(=O)c1cccc(OCC2CCOCC2)c1
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
BH3-Me2S (0.43 g, 5.8 mmol) was added dropwise to a solution of ketonitrile (13) (0.5 g, 1.9 mmol) in THF (50 mL). The reaction mixture was heated at 65° C. under reflux for 18 h. After completion of the reaction (as monitored by TLC) the reaction mixture was quenched by MeOH (15 mL) and stirred at rt for an additional 1 h. The reaction mixture was concentrated and purification by column chromatography (100-200 silica mesh, 4-6% MeOH in DCM) gave Example 2 as a pale yellow semi-solid. Yield (0.48 g, 96%); 1H NMR (400 MHz, DMSO-d6) δ 7.80 (bs, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.89-6.87 (m, 2H), 6.82-6.80 (m, 1H), 5.54 (bs, 1H), 4.65 (bs, 1H), 3.87 (dd, J=11.4, 2.8 Hz, 2H), 3.81 (d, J=6.4 Hz, 2H), 3.37-3.30 (m, 2H), 2.87-2.79 (m, 2H), 2.02-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.65 (m, 2H), 1.34-1.27 (m, 2H); RP HPLC: tR=3.89 min, 95% (AUC); ESI MS m/z 266.27 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccccc2N)cc1
Yield: 97.4 %

Procedure:
33.1 g (0.3 mol) of 1,2-phenylenediamine was dissolved in 200 ml of dioxane. A solution of 20.87 g (0.1 mol) of 4-methoxybenzenesulfonyl chloride in 110 ml of dioxane was added thereto under stirring. The resulting mixture was stirred at room temperature overnight. 12.1 g (0.12 mol) of triethylamine was added thereto. After concentration followed by addition of an aqueous citric acid solution and ethyl acetate, the organic layer was separated, concentrated and purified by silica gel column chromatography to obtain 27.1 g of the title compound.