Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:17][C:13]1[CH:12]=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[CH:3][C:4]=2[F:18])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc(Br)cc1F
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2cccc(F)c2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (ii) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>>[CH2:28]([CH:24]([NH:23][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22])[C:25]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COCOC1CCNCC1
Product: COCOC1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Methoxymethoxy-piperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([SH:40])[NH:37][C:36]=2[CH:41]=1>C(O)(C)C.CN(C)C=O>[ClH:1].[CH3:9][C:8]1[C:3]([CH2:2][S:40][C:38]2[NH:39][C:35]3[CH:34]=[CH:33][C:32]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[CH:41][C:36]=3[N:37]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Sc1nc2ccc(-c3nccs3)cc2[nH]1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1nc2cc(-c3nccs3)ccc2[nH]1
Product: Cl
Yield: 62.2 %

Procedure:
0.77 g (1.87 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitro-imidazo[1,2-b]pyridazine and 0.35 g (1.5 mmol) of 6-thiazol-2-yl-1H-benzimidazole-2-thiol in 25 ml of isopropanol and 20 ml of dimethylformamide are reacted as described in Example 2. 0.60 g (62%) of the title compound of m.p. 232-234° C. is isolated.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[N:16]1([C:2]2[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: CCOC(=O)c1oc(N2CCCCC2)nc1C(F)(F)F
Temperature: 120 °C
Yield: 88 %

Procedure:
To a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (0.85 mL) in α,α,α-trifluorotoluene (10 mL) at RT was added piperidine (1.1 mL). The reaction mixture was heated at 120° C. for 20 min by microwave then cooled to RT and diluted with EtOAc (100 mL). The organic solution was washed with H2O (2×100 mL), saturated NH4Cl (1×100 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated to give ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A-3) as a yellow solid (1.28 g, 88% yield). LCMS (ESI) calcd for [M+1]+ 293.1. found 293.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:31])[NH:20][C@:21]3([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]3C=C)[N:16]([C:32](=[O:61])[C@@H:33]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:34][CH2:35][N:36]([CH2:49][CH2:50][CH:51]=[CH2:52])[S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-:48])=[O:47])(=[O:39])=[O:38])[CH2:15]1)=[O:12])[CH2:6]2>C1(C)C=CC=CC=1.ClC1C=CC(OC(C)C)=C(C=1)C=[Ru](Cl)(Cl)C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C>[C:57]([O:56][C:54]([NH:53][C@H:33]1[CH2:34][CH2:35][N:36]([S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N+:46]([O-:48])=[O:47])(=[O:38])=[O:39])[CH2:49][CH2:50][CH:51]=[CH:52][C@@H:22]2[CH2:23][C@@:21]2([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:20][C:19](=[O:31])[C@@H:17]2[CH2:18][C@@H:14]([O:13][C:11]([N:5]3[CH2:4][C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:6]3)=[O:12])[CH2:15][N:16]2[C:32]1=[O:61])=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2[Ru](Cl)(Cl)=Cc2cc(Cl)ccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Temperature: 68 °C
Reaction time: 2 h

Procedure:
(3R,5S)-1-((S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino) butanoyl)-5-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate (1.65 g, 1.89 mmol) in toluene (400 mL) was degassed by bubbling a stream of nitrogen through the reaction for 1 hr at rt. (5-chloro-2-isopropoxybenzylidene)(1,3-dimesitylimidazolidin-2-yl)ruthenium(V) chloride (0.025 g, 0.038 mmol) was added to the mixture and the mixture was heated to 68° C. (oil bath) and stirred at this temperature for 2 hrs. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:1) to give (2R, 6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-14a-carboxylate as off white solid (1.45 g, 91%). MS: Calcd.: 842. Found: [M+H]+ 843
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:9]([CH3:24])[CH:8]=1>C1COCC1.O>[C:20]([O:19][C:17]([CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:25])=[O:5])=[CH:8][C:9]=1[CH3:24])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: COC(=O)c1ccc(OCCCC(=O)OC(C)(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
Lithium hydroxide monohydrate (137 mg, 3.26 mmol) was added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid methyl ester from Example E42.2 (414 mg, 1.34 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 48 h at room temperature and concentrated in vacuo. The residue was dissolved in chloroform, acidified with 1M HCl then washed with brine, dried and concentrated in vacuo to yield the title compound (275 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].[C:19]([O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([CH3:22])([CH3:21])[CH3:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:19]([O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH:16]([CH3:18])[CH3:17])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:43][CH:44]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)oc2ccc(Cl)c(OC(C)C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
To 80 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid was added 121 mg of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, 159 mg of BOP, 46 mg of N,N-diisopropylethylamine and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. The mixture was addedbrine and was extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent and purification of the residue by column chromatography on silica gel gave 178 mg (98% yield) of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as a colorless semi-solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].CCC[CH2-].[C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CCOC(C)=O>C1COCC1.O>[OH:13][C:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: c1cscn1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Thiazole (100 mg, 1.175 mmol) was dissolved in THF (11 mL) and cooled to a temperature of −78° C. N-butyllithium (2 M in hexanes, 0.587 mL, 1.175 mmol) was added and the mixture was allowed to stir for 30 minutes at −78° C. A solution of trans-butyl 4-acetylcyclohexanecarboxylate (319 mg, 1.410 mmol) in THF (1 mL) was then added to the mixture, and the combined solution was allowed to stir for 1 hour at −78° C. The reaction was diluted with water, warmed to 23° C., and transferred to a separatory funnel containing EtOAc. The layers were separated and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to afford butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calc'd. for C16H26NO3S [M+H]+ 312. found 312.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[CH3:26][S:27]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C(C#N)=C2C=CC(=NO)C=C2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)c1
Temperature: 0 °C
Yield: 48.6 %

Procedure:
25 g (0.11 mol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(3-methylphenyl)-acetonitrile are dissolved in 150 ml of THF and cooled in an ice bath. After adding 22 ml (0.16 mol) of triethylamine to the solution, 9.0 ml (0.12 mol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 16.8 g (51%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-(3-methylphenyl)-acetonitrile are obtained in the form of yellow crystals having a melting point of 159-161° C. (dec.).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:12])[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[N:1]1([C:6]2[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=[CH:8][N+:7]=2[O-:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [O-][n+]1ccccc1-n1ccnc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c(-n2ccnc2)c1
Temperature: 130 °C

Procedure:
A 3.22 g portion of 2-(1-imidazolyl)pyridine N-oxide was added to 7.6 g of concentrated sulfuric acid, a mixed solution of 5.2 g of fuming nitric acid and 2.6 g of concentrated sulfuric acid was gradually added dropwise thereto, and then the mixture was heated at 130° C. for about 2.5 hours. The reaction mixture was spontaneously cooled, poured into 150 g of ice-cooled water, neutralized with potassium carbonate and then extracted with 300 ml of ethyl acetate. The organic layer was dried and then concentrated, and the thus obtained mixture was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (200:0.9:0.1, v/v/v) to obtain 0.12 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][CH:32]1[CH2:37][NH:36][CH2:35][CH:34]([CH3:38])[NH:33]1>>[CH3:38][C@H:34]1[NH:33][C@@H:32]([CH3:31])[CH2:37][N:36]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:35]1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC1CNCC(C)N1
Product: C[C@@H]1CN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)C[C@H](C)N1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 2,6-dimethylpiperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.C(N1CCOCC1)C.Cl.Cl.[NH2:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41]>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41])=[O:19])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3.18 g. of N-benzyloxycarbonyl-L-isoleucine were dissolved in 25 ml. of dry tetrahydrofuran and cooled to -10° C. 1.57 ml. of isobutylchloroformate and 1.52 ml. of N-ethylmorpholine were added and the resulting solution was stirred at -10° C. for 20 minutes. 4.24 g. of 2-amino-N-(4-bromo-2-picolinoylphenyl)-acetamide dihydrochloride, prepared as described in part A)i) of Example 1, were added an the resulting suspension was cooled to -20° C. 3.13. ml. of N-ethylmorpholine in 25 ml. of dimethylformamide were added to the vigorously stirred suspension over a period of 0.5 hour. The resulting mixture was stirred at -20° C. for a further 40 minutes and left at room temperature overnight. The product was worked up in a manner analogous to that described in part A)ii) of Example 1. Recrystallisation from ethanol yielded 4.2 g (60%) of (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 714°-176° C.
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(O[C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.[NH2:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:29])=[O:28])[CH:24]=[CH:23]C=1O.Cl>C1COCC1>[CH3:29][C:27]([C:25]1[CH:24]=[CH:23][C:14]2[O:13][C:12](=[O:18])[NH:20][C:21]=2[CH:26]=1)=[O:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc(O)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 ml of triethylamine and 2.75 g (0.0093 mol) of triphosgene are added to a mixture of 4.2 g (0.0277 mol) of 2-amino-4-methylcarbonylphenol in 100 ml of THF, at 0° C. The mixture is stirred at room temperature for 1 hour, poured into 100 ml of a 0.5N HCl solution and extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated off. The compound of the title is obtained.
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>C1C=CC=CC=1>[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:1])=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: N
Reactant: O=C(Cl)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: c1ccccc1
Product: NC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A strong stream of dry ammonia is passed (for 15 minutes) into a solution of 16.5 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid chloride in 150 ml of absolute benzene under anhydrous conditions, whilst stirring. The product formed is now filtered off and washed with ehter. Recrystallisation from a large amoumt of acetone yields pure 4-[4-(1-adamantyl)-phenoxy]-butyric acid amide of melting point 176°-177° C (needles).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:22][C:19]([F:21])([F:20])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[CH2:6][CH2:7]2)=[C:13]([CH2:31][CH2:32][CH3:33])[CH:14]=1)([OH:27])[C:23]([F:24])([F:25])[F:26]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:7]1([N:6]2[C:2]([NH:1][S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])=[CH:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (498 mg) synthesized according to the method described in WO2004/98589 and 4-dimethylaminopyridine (21 mg) were dissolved in pyridine (10 mL), and benzenesulfonyl chloride (461 mg) was added at room temperature. After stirring at 85° C. for 8 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→ethyl acetate), and the obtained solid was washed with a mixed solvent of diisopropyl ether and ethyl acetate to give the title compound as a brown powder (yield 445 mg, yield 69%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C(O)C>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: NNCc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
To a solution of (4-fluorobenzyl)hydrazine dihydrochloride (1.0 g, 4.7 mmol, Matrix) in ethyl alcohol (2 mL) was added 4,4-dimethyl-3-oxopentanenitrile (0.6 g, 4.7 mmol, Aldrich). After stirring at 85° C. for 2 h, the reaction mixture was cooled, concentrated, diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 1.3 g (99%) of the title compound. MS (ESI+) m/z 248 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=2)[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[N:29][C:30]([C@@H:33]([NH2:35])[CH3:34])=[N:31][CH:32]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:35][C@H:33]([C:30]2[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=2)[CH3:34])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 29, 44.1 mg, 0.112 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 39.5 mg, 0.223 mmol), and DIPEA (0.062 ml, 0.352 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (48.6 mg, 87%). LC-MS, 501 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 8.21 (s, 1H), 5.60 (s, 1H), 5.04-5.06 (m, 1H), 3.76 (s, 3H), 2.80 (s, 3H), 2.70 (s, 6H), 1.59 (d, 3H).