Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1.[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34](O)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([N:31]([CH2:33][C:34]([NH:1][C:2]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1)=[O:35])[CH3:32])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(N)CCc2cc(OC)c(OC)cc2C1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)CN(C)C(=O)OCc2ccccc2)CCc2cc(OC)c(OC)cc2C1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a solution of ethyl 2-amino-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (430 mg, 1.5 mmol), N-benzyloxycarbonylsarcosine (357 mg, 1.6 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride in dichloromethane (5 ml) was added triethylamine (160 mg, 1.6 mmol) under stirring at 0° C. After stirring for 2 hr, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 1N hydrochloric acid, sat. sodium bicarbonate, sat. sodium chloride, dried, and evaporated. The residue was purified with silica gel column chromatography [eluent; hexane-ethyl acetate (1:1 to 1:2)] to give the titled compound (550 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:34]([O-])=O)=[C:14]([CH:33]=2)[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[N:6][CH:7]=1>[Pt].C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:33]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[C:13]([NH2:34])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)c2)nc1
Agent: [Pt]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ccc(N)c(NCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)c2)nc1
Reaction time: 24 h
Yield: 97.3 %

Procedure:
To a high pressure reactor were added 5-((5-methylpyridin-2-yl)methoxy)-2-nitro-N-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)aniline (147 g, 297 mmol), 5% Pt/C (23.2 g, 2.97 mmol), and THF (2.5 L). The reactor was flushed with nitrogen and then stirred under an atmosphere of H2 (135 psi) for 24 h. The mixture was then filtered through celite and the filtrate was concentrated to dryness to afford the title compound as a tan solid (134 g, 97%). MS (ESI): mass calcd. for C27H24F3N3O, 463.2; m/z found, 464.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.42-8.35 (m, 1H), 7.69 (s, 4H), 7.60-7.53 (m, 2H), 7.50-7.44 (m, 3H), 7.37 (d, J=8.0, 1H), 6.66 (d, J=8.3, 1H), 6.38 (d, J=2.7, 1H), 6.27 (dd, J=8.3, 2.7, 1H), 5.08 (s, 2H), 4.36 (s, 2H), 4.13 (bs, 1H), 3.05 (bs, 2H), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:13]=[CH:12]/[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8]1
Reactant: Brc1cccc2cc[nH]c12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cccc2cc[nH]c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
7-Bromoindole (5.0 g, 25.5 mmol), methyl acrylate (4.6 ml, 51.1 mmol), triphenylphosphine (0.55 g, 2.10 mmol), N,N-diisopropylethylamine (5.8 ml, 42.3 mmol), and palladium (II) acetate (0.25 g, 1.11 mmol) were added to N,N-dimethylformamide (50 ml), and the mixture was stirred at 70° C. for 18 hours under a stream of nitrogen. After cooling to room temperature, methyl acrylate (4.6 ml, 51.1 mmol), triphenylphosphine (0.55 g, 2.10 mmol), and palladium (II) acetate (0.25 g, 1.11 mmol) were added to the reaction mixture, and the mixture was stirred at 75° C. for 47 hours under a stream of nitrogen. After cooling to room temperature, methyl acrylate (7.0 ml, 77.7 mmol), triphenylphosphine (0.88 g, 3.36 mmol), and palladium (II) acetate (0.40 g, 1.78 mmol) were added to the reaction mixture, and the mixture was stirred at 100° C. for 95 hours under a stream of nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the obtained residue, a hexane/ethyl acetate mixed solution (1:1, 300 ml) was added, and the organic layer was washed with water. The obtained aqueous layer was subjected to extraction with a hexane/ethyl acetate (1:1) mixed solution, and the combined organic layer was washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=6:1) to obtain 2 (E)-methyl 3-(1H-indol-7-yl)acrylate (3.46 g, 67%) as a pale yellow-brown solid. ESI-MS: m/z 202 [M+H]+. 1H-NMR (CDCl3) δ: 3.85 (3H, s), 6.52 (1H, d, J=16.0 Hz), 6.62 (1H, dd, J=2.9, 2.0 Hz), 7.16 (1H, t, J=7.6 Hz), 7.28 (1H, t, J=2.9 Hz), 7.43 (1H, d, J=7.6 Hz), 7.71 (1H, d, J=7.6 Hz), 8.04 (1H, d, J=16.0 Hz), 8.59 (1H, br s).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:12][C:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][N:14]=1.S(=O)(=O)(O)[OH:23].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:12][C:13]1[C:17]2[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][C:16]=2[S:15][N:14]=1
Reactant: O=S(=O)(O)O
Reactant: Clc1nsc2c1CCCC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2snc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium dichromate (4.4 g) in glacial acetic acid (30 mL) was added dropwise over 1 h to a solution of 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazole 23a (2.7 g) and concentrated sulfuric acid (1.8 mL) in glacial acetic acid (80 mL). The reaction mixture was stirred at room temperature for an additional 2 h, and neutralized with a saturated solution of sodium hydrogencarbonate. Extraction with ether (3×150 mL), drying and evaporation gave an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1:1) eluted first 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-7-one (680 mg). The later fractions contained the title compound (780 mg). Mp 84-85° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[NH:23][C:22]2=[O:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[O:33].O>C1C=CC=CC=1>[OH:33][CH:32]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:30])[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: CC#CCSC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
3-(Triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (1.03g) and t-butyl glyoxalate (3.3g) were refluxed in dry benzene (50ml) with provision for the removal of water. After one hour the benzene solution was washed 5 times with water, dried and evaporated. Chromatography of the residue on silica -H gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous white solid (0.978 g) νmax (CHCl3) 3400, 1765, 1730 cm-1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:18][CH2:19][CH3:20])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=1>>[CH3:24][O:23][CH2:22][CH2:21][N:17]([CH2:18][CH2:19][CH3:20])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:25][C:26]4[C:35]([O:36][CH3:37])=[CH:34][C:29]5[NH:30][C:31](=[O:33])[S:32][C:28]=5[CH:27]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (272 μmol) (RS)-4-chloro-N-(2-methoxyethyl)-N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 87a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 11.7 mg (8%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH3:28][O:29][CH2:30][C@H:31]([NH2:34])[CH2:32][CH3:33].Cl>>[F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:34][C@@H:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1
Reactant: CC[C@@H](N)COC
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Agent: Cl
Product: CC[C@H](COC)Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-]
Yield: 37 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.2 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-methoxymethyl-propylamine.HCl (0.34 g, 2.4 mmol) were treated substantially as described in Part C of Example 19a to produce 0.16 g (37%) of crude (R)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[CH:13][N:14]=[N:15][C:16](O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20].C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:20][C:16]1[N:15]=[N:14][CH:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Oc1nncc2c1cnn2-c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncc3c(Cl)nncc32)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-ol (1.30 g, 5.65 mmol), and POCl3 (25 mL) is warmed at 100° C. After 4 hours, the reaction mixture is cooled to room temperature and added dropwise to ice cold water, followed by periodic addition of crushed ice to control the exotherm. To the aqueous solution is added EtOAc and the mixture is neutralized with sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with EtOAc (3×50 mL). The combined organic layers are washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine (2×30 mL), dried over magnesium sulfate, filtered and concentrated to afford 4-chloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazine, which is used without purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CON(C)[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31]>C(OCC)C.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:23]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[O:32])[CH3:2]
Reactant: CON(C)C(=O)c1ccc(Cl)cc1F
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 142.3 %

Procedure:
A stirred solution of 10.6 g of 2-bromobenzaldehyde diethyl acetal in 100 ml of diethyl ether was cooled to −40° C. To this cold solution was added rapidly 46 ml of a 1.2 M solution of butyllithium in hexane. The solution was warmed to 0° C. over 30 min. The solution was cooled down to −40° C. and a solution of 11.9 g of N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide in 100 ml of diethyl ether added by cannular. The solution was warmed to 0° C. and stirred for 0.75 h then quenched by the addition of 100 ml of water and 200 ml of ether added. The organic layer was separated and the aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 19.6 g of crude [2-(diethoxymethyl)-phenyl](4-chloro-2-fluorophenyl)-methanone as a gum, GC-M.S. (E.I.) (M/Z): 336 [M]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[O:12][CH2:13][CH2:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[N:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:11]=[C:10]4[O:12][CH2:13][CH2:14][C:9]4=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCC3
Reactant: NCCCN1CCOCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCC3
Yield: 85.8 %

Procedure:
A solution of chloride 196 (850 mg, 3.8 mmol) and 3-(4-morpholinyl)propylamine (1.7 mL, 11.5 mmol) in DME (30 mL) was stirred at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1-oxide 199 (1.08 g, 85%) as a yellow solid: mp 142-144° C.; 1H NMR δ 7.52 (s, 1H, H-9), 7.41 (s, 1H, H-5), 5.97 (br s, 1H, NH), 4.67 (t, J=8.3 Hz, 2H, H-7), 3.75 (t, J=4.7 Hz, 4H, 2×CH2O), 3.56 (dt, J=6.4, 5.9 Hz, 2H, CH2N), 3.35 (dt, J=8.3, 1.2 Hz, 2H, H-6), 2.42-2.53 (m, 6H, 2×CH2N, CH2), 1.83 (p, J=6.5 Hz, 2H, CH2); 13C NMR δ 158.3, 151.4, 146.1, 140.5, 128.7, 121.8, 96.7, 71.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 29.7, 25.4; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C16H21N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 58.0; H, 6.0; N, 21.2%.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18][CH2:2][C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(CO)c(C)n(C)c1C
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CCl)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.0 g of ethyl 4-(hydroxymethyl)-1,2,5-trimethyl-pyrrole-3-carboxylate is dissolved in 15 ml of benzene and 0.6 g of thionyl chloride is added dropwise and after total addition the reaction mixture is stirred for 3.5 hours at ambient temperature. The benzene is removed in vacuo leaving the gray solid, ethyl 4-(chloromethyl)-1,2,5-trimethylpyrrole-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].Cl.[NH2:33][OH:34].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:33][OH:34])=[NH:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanamide (0.300 g, 0.67 mmol), hydroxylamine hydrochloride (0.117 g, 1.69 mmol), and DIPEA (0.117 mL, 0.67 mmol) in MeOH was allowed to stir at rt overnight. The mixture was concentrated and purified by column chromatography to give A-85 (68 mg). 1H NMR (300 MHz, d6 DMSO) δ: 10.48 (br s, 1H), 10.17 (br s, 1H), 8.50 (d, 1H), 8.14-8.20 (m, 1H), 7.77-7.85 (m, 1H), 7.60-7.66 (m, 1H), 7.50-7.56 (m, 1H), 7.39-7.47 (m, 1H), 7.20-7.26 (m, 1H), 7.01-7.13 (m, 3H), 2.92-3.01 (m, 2H), and 2.65-2.72 (m, 2H). LCMS, FA: Rt=1.98 min, [MH+ 479.3].
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:43]=[N+:44]=[N-:45])=[O:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoic acid (1.67 g, 4.2 mmol), diphenylphosphoryl azide (1.26 g, 4.58 mmol) and triethylamine (0.5 g, 5 mmol) in 10 mL of dry t-BuOH was heated to 75° C. for 90 min, resulting in dissolution of the starting acid and subsequent precipitation of the azide. The cooled solution was then poured onto 10 g of ice, and the resulting mixture was filtered and dried to furnish 0.80 g of the azide as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 399.2 (M+H); mp 175° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][C:7]2=[O:8].[CH3:22][O-].[Na+]>CO>[CH2:15]([O:14][CH2:13][C:5]1[NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([C:7]([O:6][CH3:22])=[O:8])[C:3]=2[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[O-]
Reactant: Nc1cccc2c(=O)oc(COCc3ccccc3)cc12
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(COCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-amino-3-benzyloxymethylisocoumarin (800 mg) and sodium methylate in methanol (768 mg) was stirred at ambient temperature for 20 minutes. After removal of solvents, water (40 ml) was added to the residue and the whole was extacted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated to dryness to leave a crude product, which was purified by silica gel column chromatography with n-hexane:ethyl acetate (6:1) as an eluent to afford methyl 2-benzyloxymethylindole-4-carboxylate (660 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Product: O=C(c1ccc(S(=O)(=O)c2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to the procedures found in Intermediate 6 and Example 17 using 4-(phenylsulfonyl)-benzoic acid [CAS# 5361-54-6] and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)s1

Procedure:
The title compound was prepared from 2′-iodo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.98) (0.494 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.360 g, 62%). MS (ISP) 586.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 ml). At room temperature, ethyl chloroformate (32 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 86% of theory).
Reaction SMILES: CO.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][C:6](=[N:21]O)[C:5]1=[O:23]>C(O)C.[Ni]>[NH2:21][CH:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]1=[O:23]
Reactant: Cn1c(=O)c(=NO)nc(-c2ccccc2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reaction time: 30 h
Yield: 95 %

Procedure:
A solution of 150 ml of methanol containing 5 g (17.9 mmole) of 1,3-dihydro-1-methyl-3-oximino-5-phenyl-1,4-benzodiazepin-2-one was treated with a slurry of active Raney-nickel catalyst1 in ethanol (10 g wet weight). The resulting suspension was hydrogenated on a Parr apparatus at 60 psi and 23° C. for 30 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford the title compound in 95% yield.