Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl/[C:44](/[C:47]1[CH:52]=[CH:51][C:50]([C@@H:53]2[CH2:58][O:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:49][CH:48]=1)=[N:45]\[OH:46]>C1COCC1>[C:8]([O:12][C:13]([N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])[C:23]1[C:28]([C:29]2[O:46][N:45]=[C:44]([C:47]3[CH:48]=[CH:49][C:50]([C@@H:53]4[CH2:58][O:57][CH2:56][CH2:55][N:54]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:51][CH:52]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(/C(Cl)=N/O)cc1
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
Et3N (54.34 mg, 74.85 μL, 0.5370 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 4 (224.5 mg, 0.4475 mmol) and tert-butyl (3R)-3-[4-[(Z)—C-chloro-N-hydroxy-carbonimidoyl]phenyl]morpholine-4-carboxylate 13 (183 mg, 0.5370 mmol) in THF (4 mL) and the resulting solution stirred at rt for 30 min and then heated at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica, using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-50% EtOAc, 8 g column) Product began to elute at 33% EtOAc. Product fractions were combined and concentrated in vacuo to leave the product as a cream coloured solid (144 mg, 40% yield); 1.20 (6H, d), 1.30 (18H, s), 1.42 (9H, s), 3.07 (1H, m), 3.50-3.60 (3H, m), 3.73-3.85 (3H, m), 4.32 (1H, m), 5.06 (1H, s), 7.53 (2H, m), 8.07 (5H, m), 8.64 (2H, m) and 9.51 (1H, s) ppm
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[N:29][N:30]([CH2:32][CH:33]5[CH2:37][O:36]C(C)(C)[O:34]5)[CH:31]=4)[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[N:29][N:30]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])[CH:31]=4)[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(Cn2cc(Nc3ncnc(N4CCN(c5ncc(Cc6ccccc6)cn5)CC4)n3)cn2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: OCC(O)Cn1cc(Nc2ncnc(N3CCN(c4ncc(Cc5ccccc5)cn4)CC3)n2)cn1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A solution of 4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (200 mg, 0.3 mmol), and p-TSA (40 mg, 0.2 mmol) in dichloroethane (2.5 mL) was stirred at 80° C. under N2 overnight. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and diluted with ethyl acetate (40 mL). The organic phase was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give 3-(4-(4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)propane-1,2-diol (13.8 mg, yield 7%) as a white solid. MS (ES+) C24H28N10O2 requires: 488, found: 489 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:45])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:21]1[N:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[N:32][C:33]([N:36]4[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]4)=[N:34][CH:35]=3)[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[CH3:44])[C:11]([O:13]CC1C=CC=CC=1)=[O:12].O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[F:45][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:21]1[N:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[N:32][C:33]([N:36]4[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]4)=[N:34][CH:35]=3)[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[CH3:44])[C:11]([OH:13])=[O:12]
Reactant: Cc1nc2ccc(-c3cnc(N4CCNC(=O)CC4)nc3)cn2c1C(C(=O)OCc1ccccc1)c1ccccc1OC(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cnc(N4CCNC(=O)CC4)nc3)cn2c1C(C(=O)O)c1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of Example 311 (0.219 g, 0.358 mmol) in THF (4 mL) was added lithium hydroxide monohydrate (0.03 g, 0.716 mmol) and the mixture was stirred at room temperature for 4 h. The pH of the mixture was adjusted to ˜6 by the dropwise addition of a 10% aqueous solution of citric acid. The material was concentrated in vacuo, and the residue was washed with acetone, to furnish the title compound (0.135 g, 72%). δH (300 MHz, DMSO-d6) 8.57 (m, 3H), 7.66 (m, 1H), 7.51 (m, OH), 7.41 (dd, OH, J 9.3, 1.5 Hz), 7.23 (m, 1H), 7.09 (m, 2H), 6.99 (m, OH), 5.31 (m, OH), 3.95 (d, 4H, J 3.9 Hz), 3.20 (m, 2H), 2.25 (s, 3H). LCMS (pH 10): MH+ 523.2, RT 1.05 minutes.
Reaction SMILES: [CH:1]([C:3]1C=C[C:6]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)=O.Br[Zn]C1CCCC1>C1COCC1.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>[CH2:3]1[CH2:1][CH:6]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])[CH2:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2ccc(C=O)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br[Zn]C1CCCC1
Solvent: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)C1CC=C(C2CCCC2)CC1
Yield: 44.7 %

Procedure:
Prepared as in Example 14, using 100 mg (0.25 mmol) of the material prepared in step A of Example 13, 1.25 ml of a 0.5 M solution of bromo cyclopentylzinc (0.63 mmol) and 9 mg (0.012 mmol) of bis(triphenylphosphine)palladium chloride in 1 ml of THF. Afforded 35 mg (45%) of the title compound. Ion Electrospray Mass Spectrum: M+1=314.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[C:6]([OH:12])[C:5]=2[CH3:13].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].Cl>CC#N>[C:19]([Si:23]([CH3:25])([CH3:24])[O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[C:2]([CH3:1])[CH2:3]2)=[CH:8][C:7]=1[CH3:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1=Cc2cc(C)c(O)c(C)c2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC1=Cc2cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Mixture of 2,5,7-trimethyl-1H-inden-6-ol (1.8 g, 10.3 mmol), imidazole (1.76 g, 25.8 mmol), and tert-butylchlorodimethylsilane (1.87 g, 12.4 mmol) in CH3CN (35 ml) was stirred for 16 h at room temperature, poured into 2% HCl (100 ml), extracted by pentane (4×20 ml). Combined organic fraction was washed by water, dried over MgSO4, and evaporated. The yield 2.8 g (94%).
Reaction SMILES: [Se](=O)=O.[OH:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C>CC(O)C>[C:8]([C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=1[CH:5]=[O:4])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCc1ccccc1C(O)c1ccccc1
Agent: O=[Se]=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=Cc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 1 g. of selenium dioxide and 1 g. of 2-hydroxymethylbenzhydrol in 5 ml. of acetic acid was refluxed for 41/2 hours. The solution was cooled, filtered from selenium and the filtrate was poured into ice water and made alkaline with sodium hydroxide. Extraction with ether gave a yellow oil to which petroleum ether was added. White prisms were obtained which melted at 64°-67°. Ultraviolet maximum (2-propanol) at 226/7 mμ (ε = 15,750) and 251/2 mμ (ε = 18,500), inflexion at 294 mμ (ε = 2600); infrared absorption (CHCl3) at 1665 cm-1 and 1705 cm-1
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([N:35]([CH3:37])[CH3:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([N:35]([CH3:36])[CH3:37])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-dimethylamino-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (139 mg, 66%). LCMS (m/e) 524 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.15 (s, 1H), 8.34 (d, 1H, J=9.2 Hz), 8.03 (s, 1H), 7.39 (s, 1H), 7.21 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.91-6.80 (m, 2H), 6.78 (s, 1H), 6.21-6.12 (m, 1H), 3.55 (t, 2H, J=5.5 Hz), 3.38 (s, 3H), 3.02 (d, 3H, J=4.9 Hz), 3.00 (s, 6H), 2.96-2.85 (m, 4H), 2.80-2.68 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]3[C:18](=[O:21])[O:19][CH2:20][C@@H:14]3[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:22]1([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:21]=[C:18]1[N:15]2[CH2:16][CH2:17][N:12]([C:8]3[C:9]4[C:4](=[CH:3][C:2]([C:29]5[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=5[CH3:33])[C:26]([NH:25][CH:22]5[CH2:23][CH2:24]5)=[O:43])=[CH:11][CH:10]=4)[CH:5]=[N:6][N:7]=3)[CH2:13][C@H:14]2[CH2:20][O:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1OC[C@@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN4C(=O)OC[C@@H]4C3)nncc2c1
Temperature: 80 °C
Yield: 144.2 %

Procedure:
A mixture of (S)-7-(6-chlorophthalazin-1-yl)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.600 g, 1.97 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.110 g, 3.69 mmol), potassium carbonate (0.875 g, 6.33 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.136 g, 0.373 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.107 g, 0.117 mmol) in 12 mL of degassed 80% aqueous 1,4-dioxane was heated at 80° C. The crude material was purified flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→3:97) to give 1.26 g of an orange liquid. The material was further purified by reverse-phase HPLC (Phenomenex Synergi 4u MAX-RP 80, 150×21.2 mM) eluting with 0.1% formic acid-CH3CN:0.1% formic acid-H2O (1:9→9:1) to give the title compound as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.CCN(C(C)C)C(C)C.Cl[C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C1C=CN=CC=1)C.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:2]=1[NH:1][C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: COC(=O)c1cc(I)ccc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)Nc1ccc(I)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-amino-5-iodobenzoate (i-a) (15 g, 54 mmol) was added 200 mL of CH2Cl2, followed by DIEA (9.4 mL, 54 mmol) and a catalytic amount of DMAP. Ethyl 4-chloro-4-oxobutanoate (Rc═Rd═H) (8.5 mL, 60 mmol) was added, and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then poured into 250 mL H2O, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford ii-a (22 g, 99%) as a pale yellow solid: MS m/z=406 (M+H).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][N:22]=[C:23]([C:24]([O:26]CC)=[O:25])[C:17]=3[CH2:16]2)=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11]>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:17]=3[CH2:16]2)=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1noc2c1CN(C(=O)Nc1ccc(Cl)c(Cl)c1)CC2
Reaction time: 15 h

Procedure:
Lithium hydroxide monohydrate (56%) (0.25 g, 6.038 mmol) dissolved in water (8 ml) was added to a solution of ethyl 5-(3,4-dichlorophenylcarbamoyl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate (1.2 g, 3.019 mmol) in methanol (25 ml), and the mixture was stirred for 15 h. The solvent was removed in vacuo. The aqueous phase was adjusted to an acidic pH value with dilute HCl solution (aq.) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 0.94 g (87%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:33])[CH3:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH2:31][CH3:32])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CCN
Product: CCNCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.068 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.32 mmol) and ethylamine (0.138 g, 3.2 mmol). mp 138.140° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].C(O)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.C(COC)OC>[CH3:22][O:21][C:15]1[C:16]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Cc1cccc(C)c1Br
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: CCO
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 25 h

Procedure:
In an atmosphere of nitrogen, tetrakis(triphenylphosphine)palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, (5-formyl-2-methoxyphenyl)boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and dimethoxyethane, followed by stirring at 80° C. for 25 hours to obtain 6-methoxy-2′,6′-dimethylbiphenyl-3-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].[N:21]([C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])=[C:22]=[O:23]>CN(C)C=O>[C:22]([NH:21][C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)=[O:23]
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)Oc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nn(COC(=O)NC(=O)Oc2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of the alcohol of Example 41 (6.3 mg, 20 μmol) in dimethylformamide (250 μL) was treated with phenyl isocyanatoformate (3.6 mg, 22 μmol) and the mixture was shaken for 1.5 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1)=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nncs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1nncs1
Yield: 84.6 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-t-butoxycarbonyl-L-tryptophan, 3.3 g of triethylamine, 3.5 g of ethyl chlorocarbonate and 3.3 g of 2-amino-1,3,4-thiadiazole were reacted in 150 ml of chloroform to obtain 10.7 g (yield: 84%) of 2-(N-t-butoxycarbonyl-L-tryptophanylamino)-1,3,4-thiadiazole as light yellow powder of mp: 98°-101° C. (dec.) and [α]D20 : +41.0° (C=1.0, MeOH).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:45])[C@@H:13]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=[O:40])[C:29]=2[O:41][CH:42]([F:44])[F:43])(=[O:27])=[O:26])[CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.C(O)C.O.O>[Cl:23][C:20]1[S:19][C:18]([C:16]([NH:15][CH2:14][C@H:13]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=[O:40])[C:29]=2[O:41][CH:42]([F:44])[F:43])(=[O:26])=[O:27])[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:45])=[O:17])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NS(=O)(=O)c2cccc(N3CCCCC3=O)c2OC(F)F)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)N1CCC(C(=O)O)CC1)c1ccc(Cl)s1
Reaction time: 2.5 h

Procedure:
The ethyl ester (1-{(S)-3-[(5-Chloro-thiophene-2-carbonyl)-amino]-2-[2-difluoromethoxy-3-(2-oxo-piperidin-1-yl)-benzenesulfonylamino]-propionyl}-piperidine-4-carboxylic acid ethyl ester) from example 9 (128 mg, 0.185 mmol) was treated with LiOH (222 μl, 0.555 mmol, 2.5 N in water) in THF/ethanol/water (2 ml, 1 ml, 0.5 ml). After 2.5 h the reaction was brought to pH=1-2 using 2 N HCl and further diluted with 30 ml water. The product crystallized from the aq layer and can be separated by filtration. Yield: 54 mg, 44%, colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH:25]=[CH2:26])[CH:3]=1.C(Cl)Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH2:25][CH3:26])[CH:3]=1
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C

Procedure:
A mixture of 4-(4-chloro-2-vinyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo-[3,4-e][1,4]thiazepine (0.100 g, 0.26 mmol, Preparation #18) and palladium hydroxide on carbon (0.073 g, 20 wt % on dry basis, ˜0.1 mmol), in methanol (5 mL) and DCM (2 mL) was treated with hydrogen (1 atm.), at rt, overnight. Then the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method b) to give 4-(4-chloro-2-ethyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine as an off white solid: LC-MS (Table 1, Method a) Rt=4.03 min; m/z 385 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.38 (3 H, t, J=7.5 Hz) 2.71 (1 H, ddd, J=15.1, 6.3, 2.7 Hz) 2.83 (1 H, ddd, J=15.1, 8.8, 2.8 Hz) 2.94 (1 H, dq, J=15.1, 7.5 Hz) 3.10 (1 H, dq, J=15.1, 7.5 Hz) 3.18-3.27 (1 H, m) 3.52-3.60 (1 H, m) 3.79 (1 H, br s) 3.84 (3 H, s) 6.78 (1 H, s) 6.99 (1 H, dd, J=8.4, 2.2 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 0.9 Hz) 7.13 (1 H, d, J=8.4 Hz) 7.20 (1 H, d, J=2.2 Hz) 7.59 (1 H, td, J=7.8, 1.7 Hz) 7.79 (1 H, dt, J=8.0, 0.9 Hz) 8.44 (1 H, ddd, J=4.8, 1.7, 0.9 Hz).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:9]2[C:10]([C:29](=O)[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:11]3[CH:20]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][N:12]3[C:13]=2[CH:14]=[C:15]([F:17])[CH:16]=1.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[C:9]2[C:10]([C:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH2:1])=[C:11]3[CH:20]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19][CH2:18][N:12]3[C:13]=2[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)cc1)c1c2n(c3cc(F)cc(Br)c13)CCC2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (536 mg, 1.5 mmol) in THF (7 mL) at r.t. was added potassium tert-butoxide (1.5 mL, 1M THF solution). The mixture was stirred for 30 minutes at r.t. and a solution of the compound of Step 1 (190 mg, 0.38 mmol) in THF (7 mL) was added. The reaction mixture was stirred at 60° C. for 2 h, cooled and poured into aqueous saturated NH4Cl. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc/hexane to give 150 mg of the title compound.