Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:10]1([C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([O:1][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][N:5]3[C:6](=[O:16])[CH:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)nc2cc(Oc3ccccc3)ccn12
Temperature: 25 °C
Reaction time: 96 h
Yield: 9.9 %

Procedure:
8-Hydroxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.2 g, 0.81 mmol), phenylboronic acid (0.29 g, 2.4 mmol), and copper acetate (0.20 g, 1.6 mmol) were suspended in dichloromethane and treated with triethylamine (0.23 ml, 1.6 mmol) and the mixture was stirred at RT for 4 days. The product was adsorbed onto silica and eluted through a silica column with ethyl acetate to yield a pale tan solid (0.026 g).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH2:12][OH:13])=[N:8]2)[CH:2]=1.[H-].[Na+].CS([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:24][N:25]=1)(=O)=O>>[CH3:32][N:22]1[C:21]([O:13][CH2:12][C:9]2[N:10]=[N:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:14])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)=[N:25][N:24]=[C:23]1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(-n2nnc(CO)n2)c1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C)n2)c1
Yield: 52.1 %

Procedure:
The title compound (23.6 mg, 52%, white solid) was prepared from (2-m-tolyl-2H-tetrazol-5-yl)-methanol (24.8 mg, 0.13 mmol), sodium hydride (8 mg, 0.2 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (38 mg, 0.16 mmol). The product was purified by chromatography using a silica SPE tube (2.5-5% methanol in dichloromethane, desired product was second product eluting). 1H NMR (CDCl3) δ (ppm): 8.78 (m, 2H), 7.98 (s, 1H), 7.97 (d, 1H), 7.64 (d, 2H), 7.46 (t, 1H), 7.34 (d, 1H), 5.94 (s, 2H), 3.63 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](OCC)=[O:13])[N:5]=[C:4]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1>[Ni]>[CH2:21]([O:20][C:18](=[O:19])[NH:17][C:4]1[N:5]=[C:6]2[NH:11][C:12](=[O:13])[NH:8][C:7]2=[C:2]([Cl:1])[CH:3]=1)[CH3:22]
Reactant: CCOC(=O)Nc1cc(Cl)c([N+](=O)[O-])c(NC(=O)OCC)n1
Agent: [Ni]
Product: CCOC(=O)Nc1cc(Cl)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of diethyl 4-chloro-5-nitro-2,6-pyridinedicarbamate (intermediate for the preparation of 1) (500 mg) in ETOH (50 mL) was added Raney Ni (1 g) and stirred for 12 h under hydrogen atmosphere at room temperature. Reaction mixture was filtered on celite and filtrate was concentrated under reduced pressure. Residue was dissolved in 2-propanol (10 mL) and stirred for 60 h under reflux. The reaction mixture was cooled to room temperature and precipitate was filtered. The filtrate was concentrated to give 250 mg of (7-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-carbamic acid ethyl ester as a gray solid. 1H NMR confirmed the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:36]1([Zn+])[CH2:38][CH2:37]1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH:36]3[CH2:38][CH2:37]3)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]C1CC1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(C3CC3)nc2CCN1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (100 mg, 0.18 mmol, 1.00 eq.) and 0.5M cyclopropylzinc bromide in THF (0.7 mL, 0.35 mmol, 2.00 eq.) in THF (10 mL), tetrakis(triphenylphosphine) palladium (0) (10.2 mg, 9 μmol was added. The mixture was stirred at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was diluted with DCM (50 mL) and washed with water (2×25 mL). The org. layer was dried over MgSO4 and concentrated in vacuo. The residue was taken up in DMF, filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][N:3]=1.C[O-].[Na+].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:25]#[N:26])[C:6]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:12][CH:11]=2)=[O:8])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(C)nc1
Reactant: CSc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1ccc(C(C#N)C(=O)c2ccc(C)nc2)cc1

Procedure:
Under an atmosphere of nitrogen, a mixture of 38.5 g (250 mmol) of ethyl 6-methylnicotinate, 29.9 g (500 mmol) of sodium methoxide (90.5%) and 300 ml of toluene was added, at 85-90° C. and over the course of 30 min, to a solution of 47.3 g (250 mmol) of 4-(methylthio)phenylacetonitrile in 75 ml of toluene. This mixture was stirred under reflux for 14 h, then distilled until the overhead temperature exceeded 110° C. and kept at reflux for another 6 h. The reaction mixture was poured into 500 g of ice water, the organic phase was decanted off and the aqueous phase was extracted with 3×100 ml of toluene. The aqueous phase was acidified to pH 6.0 using conc. HCl. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 53.9 g (76%) of the title product in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O.CCOC(C)=O>C1COCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([NH:14][CH2:13][CH2:12][S:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(SCCN)cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)NCCSc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a cold (0° C.) solution of 2-(3,4-dimethoxy-phenylsulfanyl)-ethylamine (3.97 g, 18.6 mmol) in anhydrous THF (49 ml), were added TEA (3.11 ml, 18.6 mmol) and portionwise 3,4-dimethoxyphenylacetylchloride (4.0 g, 18.6 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was combined with H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Flash chromatography (AcOEt) gave the title product (7.08 g, 97%).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[CH:8][CH3:9])[C:5]([OH:7])=O.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[NH2:28]>ClCCl>[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[NH:28][C:5](=[O:7])[C:4]([CH2:3][CH:2]([CH3:1])[CH3:10])=[CH:8][CH3:9]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC=C(CC(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC=C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 25 °C
Yield: 99.5 %

Procedure:
2-(2-methylpropyl)-but-2-enoic acid (37 g, 0.261M) prepared as described in Example 1 in dry dichloromethane (200 ml) and N-methyl morpholine (65 ml) was treated at -5° C. with oxalyl chloride (33.2 g, 0.261M) over 30 minutes. The mixture was heated under reflux for 10 minutes, then re-cooled to ca -60° C. and O-methyl-L-tyrosine N-methylamide (51 g, 0.245M) in dry dichloromethane (100 ml) added over 30 minutes. The mixture was left to warm up to room temperature over ca 1 hour, diluted with more dichloromethane then washed with aqueous sodium hydroxide (0.1N), aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic extract was dried, then evaporated in vacuo to afford N-[2-(2-methylpropyl)-but-2-enoyl]-O-methyl-L-tyrosine-N-methylamide as a yellow gum (81 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:35][CH:34]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 4-methoxycarbonyl-phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=548.2 [M−H+]
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>CN(C)C=O>[CH3:8][N:17]1[CH:16]([C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:1]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (39 mg, 0.12 mmol) and methyl idodide (6 μL, 0.10 mmol) are added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 14, 25 mg, 61 μmol) in N,N-dimethylformamide (1 mL). The mixture is stirred at room temperature for 1 h, diluted with aceontrile and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 13 mg; ESI mass spectrum [M+H]+=427; Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: CN1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]4[N:17]([N:29]=[CH:30][N:31]=4)[C:18]([C:21]4[CH:22]=[C:23]([C:26]([NH2:28])=[O:27])[S:24][CH:25]=4)=[CH:19][N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.BrC1N2N=CN=C2C(NC2C=CC(N3CC[O:52]CC3)=CC=2)=NC=1.CC1(C)C(C)(C)OB(C2C=C(C(N)=O)SC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:5]1([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[C:16]4[N:17]([N:29]=[CH:30][N:31]=4)[C:18]([C:21]4[CH:22]=[C:23]([C:26]([NH2:28])=[O:27])[S:24][CH:25]=4)=[CH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7][O:52][CH2:3][CH2:4]1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2csc(C(N)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)cs1
Yield: 37.4 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (0.2 g, 0.53 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid amide (0.27 mg, 1.06 mmol), and Pd(PPh3)4 (0.15 mg, 0.133 mmol) in 1.5M Na2CO3 (aq) (2.84 mL, 4.26 mmol) and dioxane (10 mL). The reaction mixture is partitioned between water and ethyl acetate. A precipitate is formed, collected by filtration and purified by silica gel column chromatography using 95:5 DCM:MeOH to give the title compound (84.1 mg, 37.4%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.13 (4H, m), 3.79 (4H, m), 7.01 (2H, d), 7.60 (1H, br s), 7.91 (2H, d), 8.10 (2H, s), 8.48 (1H, s), 8.66 (1H, s), 8.79 (1H, s), 9.96 (1H, s). LCMS: Rt 2.61 min (97.1%), m/z (APCI) 422 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:19]([OH:21])[N:20]=1.P(Cl)(Cl)Cl>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) of Preparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.103 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is triturated with HOAc to yield 0.236 g of the title product as a gold solid.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]#[N:21])[CH2:16][CH2:15]3)[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1>C(O)C>[OH:2][NH:1][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:9]([C:5]([C:4]([F:23])([F:3])[F:22])=[N:6][N:7]=3)[N:10]=2)[CH2:15][CH2:16]1)=[NH:21]
Reactant: NO
Reactant: N#CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: CCO
Product: N=C(NO)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Hydroxylamine (50% w/v aqueous solution) (0.667 mL, 10.09 mmol) was added to a stirred suspension of 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carbonitrile (2.5 g, 8.41 mmol) in ethanol (16.82 mL) and the suspension was stirred at ambient temperature. Over 20 minutes the starting material largely dissolved and the product began to crystallise. The mixture was stirred for 2 hours and the precipitate was collected by filtration, washed with EtOH followed by ether and dried under vacuum to afford N-hydroxy-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboximidamide (2.410 g, 87%) as a colourless crystalline solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[C:16]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].O>CO>[CH3:11][CH:8]1[CH2:7][CH2:6][C:5]([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[C:16]([CH:30]([OH:35])[C:31]([F:32])([F:33])[F:34])[CH:15]=2)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]1
Reactant: COC(=O)C1(NC(=O)c2ccc(OCCc3cccc(C)c3)c(C(O)C(F)(F)F)c2)CCC(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(CCOc2ccc(C(=O)NC3(C(=O)O)CCC(C)CC3)cc2C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
170 mg of 4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylic acid methyl ester and 28 mg of lithium hydroxide were stirred in 50 ml of methanol and 1 ml of water for 5 h at 40° C. The reaction mixture was then diluted using 10 ml of water, the methanol evaporated and acidified to pH=2 using aqueous NaHSO4-solution. The mixture was then stirred for 30 minutes at room temperature, the product isolated by filtration and dried in vacuo to yield 138 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[CH2:7][C:8]1[C:9]([CH2:15][CH3:16])=[N:10][NH:11][C:12]=1[CH2:13][CH3:14])[CH3:4].I[CH2:19][CH3:20]>O1CCCC1>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][C:8]1[C:9]([CH2:15][CH3:16])=[N:10][N:11]([CH2:19][CH3:20])[C:12]=1[CH2:13][CH3:14])[CH3:4]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(CC)nn(CC)c1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Suspend sodium hydride (0.23 g, 5.71 mol, 60% dispersion in oil) in tetrahydrofuran (10 mL) and cool to 0° C. Add a solution of (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (1.0 g, 4.76 mmol) in tetrahydrofuran (10 mL) dropwise. After stirring at 0° C. for 30 min., add iodoethane (0.46 mL, 5.71 mmol). Allow the reaction mixture to warm to room temperature while stirring for 18 hr. Partition between ethyl acetate (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate the organic layer, dry (sodium sulfate), filter and concentrate to give (1,3,5-triethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as an oil (0.92 g, 81%). 1H-NMR (400 MHz, CDCl3) δ 4.09 (q, 2H), 4.01 (q, 2H), 3.33 (s, 2H), 2.58 (m, 4H), 1.38 (t, 3H), 1.20 (m, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cc(F)cc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.19 g, 1.07 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 0.19 g, 44%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]#[C:11][CH3:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O1CCOCC1>[CH3:12][C:11]1[O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:10]=1
Reactant: CC#Cc1cc(C#N)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of the product of Step B (0.16 g; 1.02 mmol) and 1M TBAF in THF (0.1 ml) in dioxane (3 ml) was refluxed for 1 h under N2. After cooling to room temperature the solvents were removed under reduced pressure and the residue was filtered through a small pad of SiO2, washed with fresh CH2Cl2 (3×15 ml). The combined organic phase was evaporated to dryness to give 2-methylbenzofuran-5-carbonitrile (0.16 g; 100%), as greyish solid. This was dissolved in dioxane (5 ml) and KOH (0.2 g; 3.6 mmol) was added, followed by H2O (1 ml). The resulting mixture was refluxed overnight, cooled to room temperature and solvents were removed under reduced pressure. The residue was diluted to 1 ml with H2O. The insoluble material was filtered off, washed with fresh H2O, and combined filtrates were acidified to pH˜5 with concentrated citric acid. The solid formed was filtered off, dissolved in EtOAc (10 ml), dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give title compound (0.08 g; 44%) as creamy solid. 1H-NMR (CDCl3) 2.47 (s, 3H); 6.42 (s, 1H); 7.43 (d, 1H, J=8.6 Hz); 7.99 (dd, 1H, J=1.6, 8.6 Hz); 8.26 (d, 1H, J=1.6 Hz).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].Cl.[NH:6]1[CH2:11][CH2:10][S:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13]>>[N:1]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:3]
Reactant: O=C(O)[C@@H]1CSCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: O=NN1CCSC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
NaNO2 (3.14 g) was added to the 1 mol/L HCl (33.7 mL) solution of (3R)-thiomorpholine-3-carboxylic acid (4.96 g) under a nitrogen atmosphere at 0° C. and stirred for 0.5 h. The solution was extracted with CHCl3 (5 times) and the organic layer was washed with brine. The mixture was dried over MgSO4 and concentrated under reduced pressure to afford crude (3R)-4-nitrosothiomorpholine-3-carboxylic acid as pale yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[Cl-].Br[CH2:26][O:27][C:28](=[O:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:13])[CH3:3]
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: CC(=O)OCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCOC(C)=O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Yield: 48 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.18 g) in dry DMF (3.6 ml) was ice-cooled, and thereto was added triethylbenzylammoniun chloride (0.11 g). To the mixture was gradually dropped bromomethylacetate (0.16 ml) and the mixture was gradually allowed to room temperature and stirred. Forty minutes later, thereto was added ethyl acetate, and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (ethyl acetate only) to give (acetyloxy)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g, yield 48%).