Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C1CCNC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and pyrrolidine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H33N6O4SF2 [(M+H)+] 539.2247, observed 539.2252.
Reaction SMILES: [C:1](=S)(OCC)[S-:2].[K+].[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[OH:18])=[O:10]>C(O)C>[C:9]([C:11]1[C:12]2[O:18][C:1]([SH:2])=[N:17][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:8]
Reactant: CCOC(=S)[S-]
Reactant: CC(=O)c1cccc(N)c1O
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cccc2nc(S)oc12
Yield: 92.5 %

Procedure:
Potassium O-ethyl dithiocarbonate (241 mg, 1.5 mmol) was added to a solution of 3-amino-2-hydroxyacetophenone (113 mg, 0.75 mmol) in ethanol (10 ml) and the mixture was heated to reflux for 16 hours. The reaction was concentrated, water (20 ml) was added thereto and the mixture was adjusted to pH, 3-4 with diluted hydrochloric acid. The separated matter was collected by filtration and dried by heating in vacuo to provide 134 mg (yield 92%) of 7-acetyl-2-mercaptobenzooxazole as a dark solid.
Reaction SMILES: [CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27])=[O:9])=[O:4].[C@@H:43]1([NH2:53])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)[C:3](=[O:4])[C:5]1[CH:34]=[CH:33][CH:32]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:13][C:12]=2[C:23]2[CH:24]=[C:25]([C:26](=[O:27])[NH:53][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:29]=[CH:30][N:31]=2)=[O:9])[CH:6]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reactant: N[C@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[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: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of 550 mg of 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid, 142 mg of (S)-1,2,3,4-tetrahydronaphthalen-1-amine, and 497 mg of diisopropylethylamine in 6 mL of DMF was treated with 366 mg of HATU. After stirring for 2 h the product was isolated by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. The procedure gave 220 mg of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)Cc1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cn(CCN(CC(=O)OC(C)(C)C)Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 2 (10.73 g; 31 mmol), thymine (7.88 g; 62 mmol) and potassium carbonate (8.64 g; 62 mmol) are suspended in anhydrous N,N-dimethylformamide (325 ml). The suspension is stirred at room temperature for 1 h and then at 80° C. for 6 h. The cooled mixture is codistilled repeatedly with toluene, and the residue is taken up in chloroform (500 ml) and extracted twice with water (150 ml on each occasion). The crude product is purified by chromatography on silica gel (eluent: toluene/ethanol, 27:1). Yield: 5.58 g (48%).
Reaction SMILES: CON(C)[C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[C:7]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:6]=1.[CH3:26][Si](C)(C)N[Si](C)(C)C.[Li].C[Mg]Br.Cl>C1COCC1.C(OCC)(=O)C.O>[C:4]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH:8]=[C:9]([S:11]([F:15])([F:13])([F:14])([F:12])[F:16])[CH:10]=1)(=[O:24])[CH3:26]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C

Procedure:
N-Methoxy-N-methyl-5-pentafluorosulfanyl-3-(2,2,2-trifluoroacetylamino)benzamide (20 mg) was dissolved in absolute THF (2 ml) and stirred at RT with lithium hexamethyldisilazane solution (45 μl, 1 M in THF) for 30 min. Methylmagnesium bromide solution (17 μl, 3 M in diethyl ether) was then added dropwise with stirring at 0° C. After stirring at RT for 1 h, 1N hydrochloric acid was added dropwise with cooling, followed by water and ethyl acetate. The organic phase was separated off and the water phase was additionally extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 17 mg of crude product were obtained. After further N-methoxy-N-methyl-5-pentafluorosulfanyl-3-(2,2,2-trifluoroacetylamino)benzamide (60 mg) was reacted in the manner described (crude product obtained: 60 mg), the crude products were combined and purified by means of preparative chromatography. The product-containing fractions were combined, freed from the acetonitrile, rendered basic with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 37 mg of the desired compound were obtained.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH3:29])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:26][C:24]1[CH:25]=[C:20]([S:19][C:13]2[N:12]([CH2:28][CH3:29])[C:11]([CH2:10][CH2:9][OH:8])=[N:15][C:14]=2[CH:16]([CH3:17])[CH3:18])[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CCn1c(CCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1c(CCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
In 16 ml of cocentrated hydrochloric acid was dissolved 3.8 g (8.5 mmol) of the benzyl compound (122a), and the mixture was heated at 100° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol:ethyl acetate), washed with n-hexane, and filtered to give 2.57 g of 2-[5-(3,5-dichlorophenylthio)-1-ethyl-4-isopropyl-1H-imidazol-2-yl]ethanol (123a) as crystals (yield 85%). mp 80-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:13](O)(=O)[CH3:14]>CC(C)(C)C([O-])([O-])[O-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:13]([CH3:14])[O:8][N:7]=2)[CH:9]=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1cc(C(=N)NO)cc(Cl)n1
Reactant: CC(=O)O
Agent: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1cc(-c2noc(C)n2)cc(Cl)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-hydroxy-6-methyl-isonicotinamidine (120 mg) was suspended in trimethylorthoacetate (3 ml) under inert atmosphere and acetic acid (0.3 ml) was added. The mixture was heated to 100° C. and stirred for 2 h. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and aqueous solution of NaHCO3. The organic layer was separated, washed with water and brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 9/1) affording the title compound (107 mg). HPLC (Rt)=3.17 min (method L).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[OH-].[K+].O>C(O)(C)C>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1CCN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of ethyl 1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylate (97 mg, 0.24 mmol) in isopropyl alcohol (750 μL) was added 1 N KOH (240 μL). The mixture was allowed to stir at rt for 2 h. The reaction mixture was then poured into water (20 mL) and basified to pH 9. The resultant solution was extracted with a 1:1 solution of CHCl3/isopropyl alcohol (2×30 mL). The combined organic extracts were dried, filtered, and concentrated to afford the title compound (38 mg, 43%). 1H NMR (400 MHz, CD3OD): 8.49 (d, J=4.8, 1H), 8.32 (dd, J=8.0, 1.6, 1H), 7.61-7.54 (m, 2H), 7.52-7.45 (m, 2H), 7.35 (dd, J=8.0, 4.9, 1H), 3.95 (s, 2H), 3.22-3.09 (m, 2H), 2.65-2.46 (m, 1H), 2.38-2.22 (m, 1H), 2.05-1.92 (m, 2H), 1.91-1.75 (m, 2H), 0.98-0.79 (m, 1H). MS (ESI): mass calcd for C19H19N3O3S, 369.12; m/z found, 370.2 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:32]=[C:33]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCOC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1cccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)c1

Procedure:
Following the procedure described in Example 17, Step 2, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester, [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide {4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-3-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:11])=[CH:6][CH:5]=1>CS(C)=O>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:22]=[C:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)CC1Nc2ccc(NC(=O)c3ccc(C=NN)cc3)cc2CN(CCc2ccccc2)C1=O
Solvent: CS(C)=O
Product: COC(=O)CC1=Nc2ccc(NC(=O)c3ccc(C=NN)cc3)cc2CN(CCc2ccccc2)C1=O

Procedure:
The compound of Example 8 was dissolved in DMSO and air was bubbled through the solution overnight. The mixture was quenched with ice water and filtered to give a crude solid which was flash chromatographed (octadecylsilane silica gel, 60% CH3CN/H2O/0.1% TFA) to yield the title compound. MS(ES) 498 [M+H]+, 496 [M-H]- ; Anal. (C28H27N5O4.1.85 TFA.0.25 H2O) calcd: C, 53.40; H, 4.15; N, 9.82. found: C, 53.52; H, 4.42; N, 9.72.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ncnc(Cl)c2c1
Reactant: Clc1ccc2c(c1)NCC2
Product: Cc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Yield: 15 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 15% yield from 6-chloro-indoline and 4-chloro-6-methyl-quinazoline. (M.P. 138°-41° C.; LC-MS: 296 (MH+)).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[Cl:33][C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:61])[CH3:62])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Cl)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Cl)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 132 was prepared analogous to compound of example 98 by hydrolysis of compound of example 131.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[CH:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[OH:1][C:2]1([C:13]#[N:14])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: O=C1COc2ccccc2OC1
Reactant: C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC1(O)COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4.92 g. (30 millimoles) of 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin in 100 mls. of benzene is added dropwise a solution of 30 millimoles of anhydrous hydrogen cyanide in 50 ml. of benzene. The reaction mixture is stirred overnight at ambient temperature, basified with 10% sodium carbonate solution and the organic layer separated. The benzene solution is washed once with water and dried successively over anhydrous magnesium sulfate and calcium sulfate. Evaporation of the solvent under reduced pressure at 40° C. yields the crude cyanohydrin which upon purification and mixed melting point determination gives no depression with an authentic sample of 3-hydroxy-3-cyano-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]1([S:7]([CH:10]=[CH:11][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(CCO)c1ccccc1
Reactant: Cc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1C=CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
To 0.186 g (1.0 mmol) of 2-(phenylsulfonyl)ethanol, 3 ml of acetonitrile was added, followed by 0.19 g (1.1 mmol) of methanesulfonic anhydride and 0.56 ml (4.0 mmol) of triethylamine, and the mixture was stirred for 5 hours at the internal temperature of 50° C. Subsequently, 0.19 ml (1.5 mmol) of o-iodotoluene, 0.11 g (0.05 mmol) of palladium acetate, and 0.067 g (0.22 mmol) of tri(o-tolyl)phosphine were added thereto, and the mixture was then refluxed for 16 hours. After cooled to room temperature, the reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate=80/20) to obtain 0.21 g of [2-(phenylsulfonyl)ethenyl]-2-methylbenzene. Yield: 80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][CH3:18].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:17]([CH3:18])[C:26](=[O:28])[C:25]1[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cc(OC)c(F)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)c(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
To a solution of [4-(2,4-difluoro-5-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (70 mg, 0.28 mmol) in 2.5 mL pyridine were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) (90 mg, 0.34 mmol) and POCl3 (2.3 mL) dropwise at 25° C. and the reaction mixture was stirred for 12 hours at 25° C. The solvent was evaporated, the residue was dissolved in EtOAc (15 ml) and washed with 2M aqueous HCl solution (5 mL) followed by saturated NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the title compound as a light yellow solid (40 mg, 29%). MS (ESI): m/z=501.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:25](=[O:33])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([CH2:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[CH3:41][O:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH:27]1([NH:26][C:25]([C:14]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:45]4[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=4)=[CH:22][CH:23]=3)[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:34][C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH2:12][CH2:13]2)=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(I)cc2)(C(=O)NC2CCCCC2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(CC3(C(=O)NC4CCCCC4)CCN(C(=O)[C@@H](N)Cc4cccs4)CC3)cc2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-{2-[4-cyclohexylcarbamoyl-4-(4-iodo-benzyl)-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester 1d (0.221 mmol; 0.15 g) (prepared as described in Example 1 above, substituting 4-iodobenzylbromide for 4-biphenylmethyl bromide and cyclohexylamine for cyclohexylmethylamine) and 3-methoxyphenylboronic acid (0.265 mmol; 0.04 g) in dioxane (2 mL) was added a 10% solution of sodium carbonate in water (0.53 mL), followed by 1,1′-bis-(di-t-butylphosphino)-ferrocene palladium dichloride (0.011 mmol; 7.2 mg). The resulting mixture was heated in sealed tube at 100° C. for 3 hrs. The resulting mixture was allowed to cool to room temperature and then purified via reverse phase HPLC. The desired fractions were collected and lyophilized. The resulting residue was dissolved in a 4 M HCl solution in 1,4-dioxane (3 mL) and the resulting solution was stirred overnight at room temperature. The resulting solution was then evaporated, and the residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(3′-methoxy-biphenyl-4-ylmethyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]([C:22]1[N:23]([CH3:28])[N:24]=[CH:25][C:26]=1[NH2:27])=[O:21]>>[CH3:28][N:23]1[C:22]([C:20](=[O:21])[NH:19][CH3:18])=[C:26]([NH:27][C:8]([C:6]2[C:5]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:10])[CH:25]=[N:24]1
Reactant: O=C(O)c1nc(Cl)ccc1Nc1cncnc1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(Cl)ccc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 6-chloro-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (30 mg, 0.12 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (24 mg, 0.15 mmol) according to the method described in example 64, step 6 as yellow solid (29 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:16]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:15]=3)=[N:9]2)=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[N:16]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[N:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nc(C#Cc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Cn2nc(CCc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Reaction time: 1.5 h
Yield: 51 %

Procedure:
7-chloro-2-((1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethynyl)quinoxaline (33 mg, 74.2 μmol, Eq: 1.00) was stirred in ethyl acetate (12 ml) with palladium, 5 wt % on barium sulfate, reduced (33.0 mg, 310 μmol, Eq: 4.18) under a hydrogen atmosphere for 2.5 h. Then 3 drops of acetic acid were added and stirring was continued for 1.5 h. The crude material was applied on silica gel and purified by column chromatography to give 7-chloro-2-{2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-yl]-ethyl}-quinoxaline (17 mg, 51.1%) as light red oil. MS: m/z=449.4 (M+H+)