Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].[OH:20][C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][C@H:25]([C:30](O)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23]>>[OH:20][C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][C@H:25]([C:30]([NH:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)CC=C[C@H]1c1ccccc1

Procedure:
Utilizing (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) and N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b), the title compound was synthesized using the same procedure as that described for Example 6.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:10][NH2:11])[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>O.O1CCCC1>[CH2:18]([NH:20][C:21](=[O:22])[N:10]([CH2:7][CH2:8][CH3:9])[NH2:11])[CH3:19]
Reactant: CCN=C=O
Reactant: CCCNN
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(N)C(=O)NCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred slurry of 3.35 g (20 mmol) of n-propylhydrazine oxalate and 2.24 g (20 mmol) of sodium carbonate in 50 mL of water and 10 mL of tetrahydrofuran (THF) was added 1.7 mL (21.5 mmol) of ethyl isocyanate. The mixture was stirred at room temperature for 16 h and evaporated in vacuo to leave crude 4-ethyl-2-propyl semicarbazide as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:39])=[N:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[NH2:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1
Reactant: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cnc(N)c3ccccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1cc2nc(-c3cnc(N)c4ccccc34)nc(N3CCOCC3)c2s1
Temperature: 140 °C
Yield: 5.6 %

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (63 mg, 0.20 mmol) in acetonitrile (3.6 ml) in a microwave reaction vessel was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine (110 mg, 0.40 mmol), Bis(triphenylphosphine)palladium(II) chloride (7.02 mg, 0.010 mmol) and 1M sodium carbonate in water (0.60 ml). The reaction vessel was sealed and heated in the microwave at 140° C. for 20 minutes. LC-MS of the reaction mixture showed no more starting material. The solvent was evaporated and the resulting oil was purified on silica gel (0 to 20% of 2N NH3 in MeOH/DCM). The resulting oil was further purified by reversed phase HPLC to give 141 as an off-white solid (4.7 mg, 6%) 1H NMR (DMSO d6, 400 MHz) 9.02 (d, 1H, J=8.4 Hz), 8.26 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 7.67 (t, 1H, J=7.6 Hz), 7.50 (t, 1H, J=7.6)m 7.33 (s, 1H), 7.11 (s, 2H), 5.84 (s, 1H), 3.98-3.94 (m, 4H), 3.81-3.78 (m, 4H), 1.61 (m, 6H). LCMS m/z: 422 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([O:39]C)=[O:38])#[N:2].O[Li].O.O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([OH:39])=[O:38])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
A mixture of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (51.1 mg, 0.096 mmol), LiOH—H2O-1M−H2O (191.5 μL, 0.1915 mmol), and THF (1.5 mL) was stirred at ambient temperature for 3 days. The mixture was quenched with HCl (4M in dioxane) (71.83 μL, 0.287 mmol). The crude material was purified by silica gel column chromatography to provide the desired product (0.027 g). MS (APCI)=520.2 (M+1).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:10]([OH:30])[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[OH-].[Na+]>[OH-].[OH-].[Pd+2].CO.O>[OH:30][CH:10]1[CH2:9][NH:8][CH2:29][CH2:28][C:11]21[C:15](=[O:16])[N:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=1)[CH2:13][CH2:12]2
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2O
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (5SR,6RS)-8-benzyl-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (293 mg, 0.70 mmol), acetic acid (1 ml) and Pearlman's catalyst (195 mg) in MeOH (20 ml) was stirred at room temperature under an atmospheric pressure of H2 for 4 h. The catalyst was removed by filtration and the filtrate was evaporated to give a crude residue was dissolved in water and the solution was made basic with 1N NaOH and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and evaporated under reduced pressure to yield (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as an off white solid. MS (ESI): 331.2 (MH+).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C:12]12[CH2:17][CH2:16][C:15]([C:20]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2
Reactant: O=C(NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 99.6 %

Procedure:
2-Tetrahydropyranyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (548 mg) was dissolved in ethanol (6 mL). To this solution, 10% palladium-carbon (60 mg) was added and the mixture was stirred at room temperature for 2 hours in a stream of hydrogen. The catalyst in the reaction mixture was filtered through a Celite pad and the filtered catalyst, together with the Celite pad, washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give 2-tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (357 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH:14](OC(C)C)(OC(C)C)[O:15][CH:16]([CH3:18])[CH3:17]>>[CH:16]([O:15][CH:14]=[C:4]([C:3](=[O:11])[C:2]([F:12])([F:13])[F:1])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:18])[CH3:17]
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Reactant: CC(C)OC(OC(C)C)OC(C)C
Product: CC(C)OC=C(C(=O)OC(C)C)C(=O)C(F)(F)F

Procedure:
The preparation was carried out analogously to preparation example 1 using isopropyl 4,4,4-trifluoro-3-oxobutyrate and triisopropyl orthoformate.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(Cl)c2)cn1
Yield: 4 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (5 mg, 4%) which was obtained as an off-white solid. MS: m/e=354.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[CH3:23][N:24](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][CH2:12][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:23]#[N:24])[C:3]=2[CH:4]=[CH:5][N:6]=1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(Br)cccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(C#N)cccc12

Procedure:
A microwave vial was charged with 5-bromo-1-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)isoquinoline (D11; 640 mg, 1.68 mmol), dry, degassed N,N-dimethylformamide (DMF) (8 ml), zinc cyanide (217 mg, 1.85 mmol) and tetrakis(triphenylphosphine)palladium(0) (194 mg, 0.168 mmol). The reaction vessel was sealed and heated using microwave irradiation to 120° C. for 60 min. After cooling, the mixture was diluted with ethyl acetate, the organic layers partitioned with water (×3) and the aqueous layer discarded. The organic layers were passed through a hydrophobic frit before being concentrated in vacuo. The resultant yellow oil was purified by flash column chromatography on silica using 2% to 20% ethyl acetate in cyclohexane as eluent. The relevant fractions were pooled and concentrated in vacuo to give the title compound as a yellow oil (417 mg).
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)[OH:6].[CH:10]1[C:23]2[C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH2:22]([C:23]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:25])=[O:6])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O=[N+]([O-])O
Product: O=C(O)c1ccccc1Cc1ccccc1

Procedure:
A known process involves the oxidation of mixtures of o- and p-benzyl-toluene with dilute nitric acid under pressure at temperatures of 135°-200° C. The reaction mixture is treated with concentrated sulfuric acid to effect the conversion of the o-benzolyl-benzoic acid to anthraquinone; the residual p-benzoyl-benzoic acid is extracted with a soda solution (Acta Chem. Scand. 9, 177-178, 1955; Chem. Abstr. 1956, 4080i). There is no discussion of the purity of the product, in particular with reference to the considerable quantities of nitration by-products. Repetition of the known process lead to the discovery that o-benzyl toluene is unusually susceptible to nitration during the oxidation process with nitric acid. If the oxidation is carried out in the known manner with nitric acid under pressure, only a small amount of the desired o-benzyl-benzoic acid is produced; the reaction product consists primarily of nitration products, in particular nitro-o-benzoyl benzoic acids. For this reason, it is not possible to obtain a pure anthraquinone in good yield with this procedure. If the resultant raw product is treated with sulfuric acid at elevated temperatures, the solution becomes black from the dissociation of the nitro compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl-].[Li+].O.C(OCC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([CH3:10])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 796 mg (2.55 mmol) of diethyl [2-(4-chlorophenyl)propan-2-yl]malonate, 216 mg (5.10 mmol) of lithium chloride and 46 μl (2.55 mmol) of water in 5 ml of DMSO was heated to reflux and stirred at this temperature for 4 h. After cooling to room temperature, 20 ml of diethyl ether and 20 ml of water were added to the reaction mixture. After separation of the phases, the organic phase was washed three more times with water, and the organic phase was dried over magnesium sulphate and then concentrated to dryness. The crude product was purified by preparative HPLC (mobile phase methanol/water 70:30). This gave 276 mg of the title compound (45% of theory).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:16]=1)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:14]=[N:13][CH:12]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-carbamic acid tert-butyl ester (example 39, 0.06 g, 0.151 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.151 mL, 0.604 mmol) and the reaction mixture was stirred at room temperature over night. The resulting suspension was filtered off and the solid material was triturated in diethyl ether, filtered off and further dried in a high vacuum to give the title compound (0.046 g, 91%) as a white solid. MS: 298.3 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][O:17][C:13]=3[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][O:17][C:13]=3[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)c3occc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(O)cc2)c2ccoc12
Temperature: -78 °C

Procedure:
To a 100 ml round bottom flask was added 4-(4-methoxyphenyl)-benzofuran-7-carbaldehyde (480 mg, 1.90 mmol), CH2Cl2 (12 ml), and the solution was cooled to −78° C. Then BBr3 (3.8 ml 1.0 M in CH2Cl2, 3.8 mmol) was added dropwise and the reaction was warmed to room temperature. After 1.5 h the reaction was quenched with water (15 ml), extracted with ether (3×), passed through a silica plug and concentrated to 160 mg (35%) of product as a foam. Chromatography (1:1 EtOAc:hex.) produced an analytical sample: mp 184–185° C.; 1H NMR (500 MHz, DMSO-d6): δ 6.96 (2H, d, J=8.8 Hz), 7.20 (1H, d, J=2.5 Hz), 7.52 (1H, d, J=7.7 Hz), 7.58 (2H, d, J=8.5 Hz), 7.89 (1H, d, J=7.7 Hz), 8.24 (1H, d, J=2.2 Hz), 9.84 (1H, s), 10.35 (1H, s); HRMS (ESI+) m/z 239.07027 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][CH2:14][SH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:12][CH2:13][CH2:14][S:15][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cnccn12
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCSc1ccc2cnccn12
Temperature: 0 °C
Yield: 76.5 %

Procedure:
To the solution of 2.0 g of 6-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 dissolved in 20 ml of dimethylformamide were added 1.8 g of 2-aminoethanethiol hydrochloride and 1.0 g of potassium carbonate. The reaction mixture was refluxed for 5 hours, poured into 100 ml of ice-water and then extracted with ethyl acetate (50 ml×3). The organic layer was isolated and concentrated to dryness; and the residue was chromatographed over silica gel to obtain 1.5 g of title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH2:22][CH3:23])=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@H:2]1[NH:1][C:27](=[O:29])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH2:22][CH3:23])=[N:20][O:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:25]
Reactant: CCc1noc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](CC)C4=O)cn3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-N-{6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 35) was dissolved in dichloromethane (1.0 ml) and TEA (0.004 ml, 0.03 mmol) was added. The reaction mixture was cooled down to 0° C. and triphosgene (1.3 mg, 4.49 μmol) dissolved in 0.1 ml of dichloromethane was added. The reaction mixture was stirred at that temperature for 30 minutes. The mixture was quenched with 0.5 ml of water and water was removed by addition of sodium sulphate. The organic phase was pipetted off and evaporated and the crude obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAv (from 1/0 to 7/3, then 7/3, then from 7/3 to 1/1, the 1/1, then from 1/1 to 0/1) to afford the title compound (1.3 mg).
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH3:7])=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15]C=C[CH:18]=2)[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[NH2:20][C@@H:10]1[C:11]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([OH:5])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1CCCc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@@H](O)c2ccccc21
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar; 25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately ⅓ of its volume and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was extracted into DCM (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound (41.1 g, 169 mmol, 99%). 1H NMR (400 MHz, CDCl3): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J 5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[Cl:27])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1>[Cl:27][C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[N:34]=[CH:35][S:36][CH:37]=2)=[CH:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Yield: 84.2 %

Procedure:
A mixture of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (236 mg, 0.489 mmol), 4-(tributylstannyl)-1,3-thiazole 238 mg, 0.636 mmol), lithium chloride (27 mg, 0.636 mmol) and tetrakis(triphenyphosphine)palladium (57 mg, 0.0489 mmol) in 1,4-dioxane (10 ml) was refluxed for 5 hr under nitrogen atmosphere. After evaporation, the residue obtained was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (3:4) to afford 200 mg (84%) of the title compound as a pale brown gum.
Reaction SMILES: [CH3:1][N:2]([CH3:12])/[C:3](=[C:5]1\[N:6]=[C:7]([CH3:11])[O:8][C:9]\1=[O:10])/[CH3:4].[H-].[Na+].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:9](=[O:10])/[C:5](/[NH:6][C:7](=[O:8])[CH3:11])=[C:3](/[N:2]([CH3:12])[CH3:1])\[CH3:4])[CH3:16]
Reactant: CC1=N/C(=C(/C)N(C)C)C(=O)O1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(NC(C)=O)=C(\C)N(C)C

Procedure:
4-[1-Dimethylamino-eth-(Z)-ylidene]-2-methyl-4H-oxazol-5-one (7.4 g, 44.0 mmol) was dissolved in ethanol (50 ml), and sodium hydride (0.10 g, 4.4 mmol) was added at room temperature. The dark solution was refluxed for 1 h. The solvent was evaporated, and the crude product [MS: m/e=215.5 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[O:40][C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[CH:33]=1)([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[O:40][C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[CH:33]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1cc3cnccc3o1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)c(-c1cc3cnccc3o1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 79.7 %

Procedure:
In a round-bottom flask equipped with a balloon, a mixture 2-(5-Nitro-1-trityl-1H-indazol-3-yl)-furo[3,2-c]pyridine (210 mg, 0.4 mmol) and 5% Pd on carbon (21 mg) in ethyl acetate and methanol (10 mL, 1:1) was hydrogenated overnight at room temperature to give 157 mg desired product (80% yield).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([C@@H:17]1[CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)[C:20]=2[CH2:19][CH2:18]1)[CH3:16].[NH2:41][C:42]1[C:47]([S:48]([N:51]2[CH2:55][CH2:54][C:53]([NH:57]C(=O)OC(C)(C)C)([CH3:56])[CH2:52]2)(=[O:50])=[O:49])=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[NH2:57][C:53]1([CH3:56])[CH2:54][CH2:55][N:51]([S:48]([C:47]2[C:42]([NH2:41])=[N:43][CH:44]=[C:45]([C:35]3[CH:36]=[CH:37][C:31]4[O:30][CH2:29][CH2:28][N:27]([C:21]5[C:20]6[CH2:19][CH2:18][C@H:17]([CH2:15][CH3:16])[CH2:26][C:25]=6[N:24]=[CH:23][N:22]=5)[CH2:33][C:32]=4[CH:34]=3)[CH:46]=2)(=[O:49])=[O:50])[CH2:52]1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CCC(C)(N)C5)c4)cc3C2)C1

Procedure:
Prepared as dihydrochloride salt according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)-3-methylpyrrolidin-3-ylcarbamate (reagent preparation 25) in step 1 followed by Boc deprotection. 1H NMR (400 MHz, methanol-d4): 8.50 (m, 3H), 7.70 (s, 1H), 7.50 (d, 1H), 7.07 (d, 1H), 5.23 (d, 1H), 5.13 (d, 1H), 4.57 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 3.70 (m, 3H), 3.55 (m, 1H), 3.45 (m, 1H), 2.98 (m, 2H), 2.73 (m, 1H), 2.41 (m, 1H), 2.19 (m, 2H), 2.05 (m, 1H), 1.82 (m, 1H), 1.48 (m, 4H), 1.24 (m, 1H), 1.02 (t, 3H); MS (EI) for C29H37N7O3S: 564 (MH+).