Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-methyl-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl alcohol following General Procedure J.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Br[C:41]1[C:42]([C:47]([O:49][CH3:50])=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1COCC1.O.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>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:41]5[C:42]([C:47]([O:49][CH3:50])=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=5)=[CH:27][CH:28]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: COC(=O)c1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ncccc1-c1ccc(Cn2cnc3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
The mixture of (S)—N-(1-(3-isopropylphenyl)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-5-carboxamide (94 ma, 0.18 mmol), methyl 3-bromopicolinate (20 mg, 0.09 mmol), Pd(PPh3)4 (11 mg, 0.009 mmol) and Na2CO3 (19 mg, 0.18 mmol) in DME/THF/H2O (2.5 mL/1 mL/1 mL) was heated to 100° C. and stirred for 18 hrs under N2. Then the mixture was poured into 10 mL of water, and extracted with EtOAc (10 mL×3), the combined organic layers was washed with water (10 mL) and brine (10 mL) and dried with Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. The residue was purified with prep-TLC (DCM/Methanol=20/1, silica gel) to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F-].[Cs+].C[CH:13]([OH:17])[CH:14](O)[CH3:15]>C(OCC)C.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>[CH:13]([C:14]1[CH:15]=[CH:7][C:6]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:5][CH:4]=1)=[O:17]
Reactant: CC(O)C(C)O
Reactant: N#Cc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Product: N#Cc1ccnc(-c2ccc(C=O)cc2)c1

Procedure:
Benzaldehyde-4-boronic acid (1.36 g), 2-bromo-4-cyano pyridine (1.5 g), cesium fluoride (2.72 g) and tetrakis(triphenylphosphine)palladium(0) (285 mg) were mixed together in dimethyl ethylene glycol (30 ml ). The reaction mixture was refluxed for 16 hrs under a atmosphere of nitrogen after which time the cooled mixture was diluted with diethyl ether (40 ml ) and washed with water (40 ml), the organic layer was separated and washed with saturated brine, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography eluting with Dichloromethane/Diethyl ether (97.5/2.5, v/v) to afford the title compound (0.81 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:25])=[C:22]([CH:24]=1)[NH2:23]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:25])=[C:22]([NH:23][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cc(Cl)ccc3F)c2c2ccccc12
Yield: 47.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 5-chloro-2-fluoroaniline (82 mg, 0.56 mmol) to provide 205 (70 mg, 48% yield) as a white solid. LC-MS (M+H=340, obsd.=340).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:27])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:40])[C:38]=1[F:39]>>[CH3:27][C@@H:12]1[CH2:13][N:14]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16][N:11]1[C:9]1[NH:8][C:7]2[C:2]([C:35]3[CH:34]=[C:33]([F:32])[C:38]([F:39])=[C:37]([F:40])[CH:36]=3)=[CH:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][C:6]=2[N:10]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
7-Bromo-2-{(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-5-(trifluoromethyl)-1H-benzoimidazole (152 mg, 0.3 mmol, Example 79) and 3,4,5-trifluorophenylboronic acid (88 mg, 0.5 mmol, Lancaster) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 560 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][CH2:18][NH:19]C(=O)C(F)(F)F)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(NCCCN1C2C=C(c3ccc(Cl)cc3)CC1CC2)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NCCCN1C2C=C(c3ccc(Cl)cc3)CC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Racemic N-{3-[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-propyl}-2,2,2-trifluoroacetamide (0.73 g, 1.96 mmol) and 20% potassium hydroxide (2.8 mL) were combined in ethanol (12 mL) and stirred at room temperature for 24 hours. Reaction was concentrated, dissolved in methylene chloride (200 mL), added sodium sulfate and stirred for 15 hours. The mix was filtered through Celite and concentrated to yield 3-[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-propylamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[C:25]([NH2:34])(=[O:33])[C:26]1[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH2:28]>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=1[C:25]([NH2:34])=[O:33])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccccc3C(N)=O)c2cc1OC
Yield: 83.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 177.0 mg (1.3 mmol) of anthranilamide to give 292.4 mg (84.0%) of the product as a deep yellow solid, m.p. 238-240.5° C., mass (electrospray, m/e): M+H 348.9.
Reaction SMILES: Cl[C@H:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[SH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[S:18][CH:2]([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: Cn1c(S)nnc1-c1cccs1
Reactant: C[C@@H](Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(Sc1nnc(-c2cccs2)n1C)C(=O)O
Reaction time: 2.5 h
Yield: 12.2 %

Procedure:
(R)-2-chloro-propionic acid (500 mg, 4.6 mmol), 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (1.09 g, 5.58 mmol) and potassium carbonate (1.94 g, 14.03 mmol) were dissolved in acetonitrile (15 ml) at room temperature. Reaction proceeded for 2.5 h and was partitioned between ethyl acetate (350 ml) and water 3 times, washed with 1 M HCl, once with saturated brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. Reaction was not completed at this stage and the crude was stirred in DMF (10 ml) overnight. Extraction was repeated and purification was performed by SPE (solid phase extraction) chromatography on silica gel using 300 ml ethyl acetate, 100 ml 1%, and 100 ml 3% formic acid in ethyl acetate, yielding title compound (150.7 mg, 12%) 1H-NMR (CDCl3), d (ppm): 7.52 (dd, 2H), 7.19 (m, 1H), 4.21 (q, 1H), 3.78 (s, 3H), 1.64 (d, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=3)[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:29]2=[O:30])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CC1c1ccc(Br)cc1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 72 %

Procedure:
To a stirred solution of 1-benzenesulfonyl-2-(4-bromo-phenyl)-aziridine (1.00 g) in tetrahydrofuran (16.5 mL) under argon were added sodium iodide (0.487 g) and phenylisocyanate (0.539 g). The mixture was stirred for 5 days at room temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The org. phase was dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>0:1) to give 1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (0.974 g) as a colorless solid. MS: 458.9 ([M+H]+)
Reaction SMILES: C[O:2][C:3]([C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C@H:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:23]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:13](/[CH:12]=[CH:11]/[C:5]3([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[CH:14][CH:15]=2)[N:20]=1)[CH3:24])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)CCCCO3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid methyl ester (130 mg, 0.3 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the organic solvent was evaporated. The solution was acidified to pH 2 with ice-cold hydrochloric acid (2 M) and the mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid (135 mg, 0.3 mmol) as a yellow gum which was used crude in the next step. LCMS (m/z) 427.1 [M+H], Tr=2.17 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:12])[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(N)nc12
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Yield: 37.8 %

Procedure:
In a dry 25 mL round bottom flask, 5-methyl-7-(3-nitro-phenyl)-benzo[1,2,4]triazin-3-ylamine (0.223 g, 0.7935 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.396 g, 1.19 mmol, 1.5 equiv), cesium carbonate (0.776 g, 2.38 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.092 g, 0.159 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.073 g, 0.079 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (10 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 5 hours, then filtered hot and the solvents were evaporated. Silica gel column purification provided desired product as a yellow powder (0.16 g, 39% yield). MS (ESI+): m/z=582.1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([F:26])[CH:10]=2)=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[F:26][C:11]1[CH:10]=[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a solution of benzyl {4-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}carbamate (32 g, 90.6 mmol) in pyridine (141 mL) was added p-toluenesulfonyl chloride (18.3 g, 108.7 mmol), and the mixture was stirred at 80° C. for 3 hr. After cooling to room temperature, pyridine was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (32.0 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.Cl.[CH3:11][NH:12][O:13][CH3:14].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNOC
Reactant: Cn1cc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnn(C)c1
Temperature: 13 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (5.0 g, 39.6 mmol), N,O-dimethylhydroxylamine hydrochloride (4.8 g, 48.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 g, 48.0 mmol), hydroxybenzotriazole (6.5 g, 48.0 mmol) and triethylamine (12.1 g, 120 mmol) in dichloromethane (100 mL) was stirred at 9-17° C. overnight. The reaction mixture was diluted with water (50 mL) and the resulting mixture was extracted with EtOAc (30 mL×3), the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo (an example of a standard aqueous/EtOAc procedure), then purified by silica gel column chromatography (PE:EtOAc=5:1) to give product (4.6 g, yield 69%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)(=[O:47])=[O:46]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NS(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:16]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:18]=[C:19]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)(=[O:12])=[O:11])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29]
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
reacting the product of step c) with 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine to form 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide,
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[C:20]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:19])[NH2:18])=[N:10]2)=[C:6]([F:23])[CH:5]=1)[CH3:2].N1CCCCC1.C[N:31](C)[CH:32](N(C)C)[CH:33]([O:36][CH3:37])[C:34]#N>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:18]=[C:32]([NH2:31])[C:33]([O:36][CH3:37])=[CH:34][N:19]=3)=[N:10]2)=[C:20]([F:22])[CH:21]=1)[CH3:2]
Reactant: COC(C#N)C(N(C)C)N(C)C
Reactant: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Solvent: C1CCNCC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3c2CCC3)c(F)c1
Temperature: 100 °C

Procedure:
4.21 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carboximidamide 1-2-1 (13.2 mmol, 1.00 eq.) were suspended in 47 mL of dry 3-methyl-1 butanole, 0.26 mL of piperidine (2.63 mmol, 0.20 eq.) and 3.09 g of 3,3-bis(dimethylamino)-2-methoxypropanenitrile 1-3-1 (18.0 mmol, 1.37 eq.) were added under nitrogen atmosphere and stirred over night at 100° C. bath temperature. The reaction mixture was cold with an ice bath the precipitate was filtered of, washed with 3-methyl-1 butanol and dried at 50° C. to give 1.77 g (4.41 mmol, 33.5%) of analytically pure target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([NH:1][C:47](=[O:48])[C:46]3[CH:50]=[C:42]([CH2:41][C:35]4[C:36](=[O:40])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[C:33](=[O:56])[C:34]=4[CH3:55])[CH:43]=[CH:44][C:45]=3[O:51][C:52](=[O:54])[CH3:53])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccnc1N1CCOCC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
3-Amino-2-morpholinopyridine (0.269 g, 1.500 mmol), triethylamine (0.197 g, 1.950 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.165 g, 0.975 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=2:1) to obtain the titled compound (0.249 g, 0.465 mmol, 62%).
Reaction SMILES: [NH:1]([C:14]([CH3:16])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:39]([O:43][C:44]([C:46]1[C:54]2[CH2:53][CH2:52][O:51][CH:50]([CH2:55][NH2:56])[C:49]=2[S:48][C:47]=1[NH2:57])=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)C(C)C)(C)C>ClCCl>[C:39]([O:43][C:44]([C:46]1[C:54]2[CH2:53][CH2:52][O:51][CH:50]([CH2:55][NH:56][C:11](=[O:13])[CH:2]([NH:1][C:14](=[O:15])[CH3:16])[CH2:3][C:4]3[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)[C:49]=2[S:48][C:47]=1[NH2:57])=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a mixture of Ac-D-Tyr-OH (235 mg, 1.05 mmol) dissolved in dichloromethane (10 ml) was added 1-hydroxybenzotriazole (0.14 g, 1.05 mmol), 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (0.20 g, 1.05 mmol) and the reaction mixture was stirred for 15 min at room temperature. 2-Amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.3 g, 1.05 mmol) dissolved in dichloromethane (10 ml) was added followed by N,N-diisopropyl-ethylamine (0.18 ml, 1.05 mmol). The resulting reaction mixture was stirred for 18 h at room temperature, diluted with dichloromethane (15 ml) was washed with 10% aqueous citric acid (25 ml), saturated sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (40 g) using ethyl acetate as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 304 mg (59%) of 7-((2-acetylamino-3-(4-hydroxy-phenyl)propionylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.