Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])([O:7]C(C)C)=[O:6])(C)C.Br[Si](C)(C)C>ClCCl>[P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])([OH:6])([OH:7])=[O:4]
Reactant: CC(C)OP(=O)(/C=C/CCOn1cnc2c(N)ncnc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCC/C=C/P(=O)(O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyloxy]adenine (105 mg, 284 μmol) in dichloromethane was added bromotrimethylsilane (0.87 g, 5.68 mmol). The resulting white suspension was stirred at room temperature under dry nitrogen for 18 hr. The solution was evaporated to dryness and the residue azeotroped with methanol (×3). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (E)-9-(4-phosphonobut-3-enyloxy)adenine as a white solid (68 mg, 84%), m.p. 249°-251° C.; λmax (MeOH) 260 (11,985)nm; υmax (KBr) 3110, 2300, 1695, 1470, 1410, 1330 and 1030 cm-1 ; δH[(CD3)2SO] 2.62 (2H, m, CH2), 4.50 (2t, t, J 7 Hz, CH2O ), 5.94 (1H, dd, J 17 Hz and 22 Hz, PCH=CH), 6.50 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz, PCH=CH), 7.39 (2H, br.s, NH2), 8.16 (1H, s, H-2/H-8), 8.35 (1H, s, H-2/H-8); FABMS (thioglycerol) 286 (MH+) (Found: C, 35.75; H, 4.00; N, 23.14; Br, 5.41%. C9H12N5O4P.0.2HBr requires C, 35.86; H, 4.08; N, 23.24; Br, 5.30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2ccccc2)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2ccccc2)nc(C(=O)O)c1=O
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a suspension of methyl 5-methoxy-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylate (39.04 g) in methanol (663 mL) was added dropwise 1N sodium hydroxide (300 mL) with stirring under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. 1N Hydrochloric acid (300 mL) was added dropwise with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The precipitated crystals were collected by filtration, washed successively with water, ethanol/diisopropyl ether (1/2), and diisopropyl ether, and dried to give the title compound (36.1 g) as pale-yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.CO>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccco2)CC1
Reaction time: 48 h
Yield: 55.7 %

Procedure:
To an equimolar solution of furan-2-carbaldehyde (250 mg, 2.6 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (473 mg, 2.6 mmol) in dichloromethane (14 mL) 1M titanium(IV) chloride in dichloromethane (1.3 mL, 1.3 mmol) and triethylamine (0.32 mL, 2.6 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere for 2 days. Then sodium cyanoborohydride (493 mg, 7.8 mmol) in methanol (7 mL) was added dropwise with stirring and the solution was allowed to stir overnight at room temperature. 35% Sodium hydroxide was added and the product was extracted with ethyl acetate. The solvent was removed under reduce pressure and the crude was purified by flash chromatography (dichloromethane/methanol 95:5) to give the title compound as a red oil (406 mg, 56%).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[CH:1]1([C:4]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(O)(c1ccc(F)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
559 mg (3.10 mmol) of the compound from Example 77A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 12 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min and then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 361 mg (38% of theory) of the title compound.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([NH:16][C:17]2[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:19]=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH:10]1([N:16]([C:17]2[N:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:19]=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1
Reaction time: 6 h
Yield: 26 %

Procedure:
Cyclohexylisocyanate (13 ul, 0.1 mmol; [3173-53-3]) was added at ambient temperature to a solution of cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (30 mg, 0.1 mmol) in toluene (0.4 ml) under an argon atmosphere. The solution was heated under reflux conditions for 12 h, cyclohexylisocyanate (7 μl, 60 μmol; [3173-53-3]) was added and heating was continued for further 6 h. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (11 mg, 26 μmol; 27%) as off-white solid. MS: m/e=417.4 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.S(Cl)([Cl:13])=O>ClCCl>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: CN(C)C(=O)COCCO
Solvent: ClCCl
Product: CN(C)C(=O)COCCCl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
40 ml of dichloromethane are transferred into a round bottom flask of 250 ml volume and 30.0 g (0.2 mol) 2-hydroxyethoxy-acetic acid-N,N-dimethylamide are added. The vessel is cooled on ice and 25.0 g (0.21 mole) of thionyl chloride are added to it dropwise in 10 minutes. The reaction mixture is stirred at room temperature for 20 minutes, and the solvent is evaporated in vacuo (260 Pa) at 50° C. Thus 33.2, g (99%) of title compound are obtained, which has higher purity than 95% by gas chromatographic analysis. Optionally the product can be purified by vacuum distillation (boiling temperature 85-86° C. at 1.3 Pa).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O.C(OC(C1C(OC)=C2C(O)=C(C#N)C=NN2C=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:32][CH:31]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1OC
Agent: CCOC(=O)c1cn2ncc(C#N)c(O)c2c1OC
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1OC
Yield: 50.3 %

Procedure:
The compound 393 was prepared from 0.37 g of crude 4-chloro-3-cyano-5-methoxy-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester and 4-phenoxy-phenylamine (0.24 g, 1.30 mmol) by a route analogous to that used for the preparation of compound 388D. 0.28 g of 393 was obtained in 49% yield for 3 steps from 393F. LCMS Found: (M+H)+=429.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Solvent: CCO
Product: CC(C)(C)c1cc(-c2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
5.0 g (1.41 mmol) of ethyl 3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-carboxylate (Chem. Lett. (1998), 9, 931-932) is dissolved in ethanol (25 ml). The solution is cooled down to 0° C. then a 1N solution of soda is added dropwise. After stirring overnight at ambient temperature, the reaction medium is heated under reflux in order to complete the reaction. After evaporation of the solvents and dilution of the residue with water, the mixture obtained is acidified with a 1N solution of HCl and extraction is carried out with dichloromethane. The organic phase is washed with sodium chloride in a saturated aqueous solution before being dried over magnesium sulphate, filtered and concentrated under vacuum. The product obtained is purified by crystallization from diisopropyl ether in order to produce a yellow-white solid with a yield of 47%. Melting point: >240° C.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Hf+4:5].[Li][Li].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=CC=1>>[CH2:12]1[C-:11]=[CH:14][CH:8]=[CH:13]1.[CH2:12]1[C-:11]=[CH:14][CH:8]=[CH:13]1.[Cl-:1].[Cl-:1].[Hf+4:5]
Reactant: Cc1ccccc1
Agent: [Hf+4]
Agent: [Cl-]
Agent: [Li][Li]
Product: [C-]1=CC=CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.81 g (5.65 mmol) of hafnium tetrachloride are added to a suspension, cooled to -78° C., of 2.00 g (5.64 mmol) of the dilithium salt (Example 4) in 150 ml of toluene. The orange suspension is allowed to warm to room temperature, and is stirred for a further 2 days in order to complete the reaction. Insoluble constituents are then filtered off via a frit, and the orange-red filtrate is evaporated to dryness on an oil pump. 30 ml of pentane are added to the orange-red residue, and the mixture is stirred vigorously overnight. Removal of the solvent in vacuo gives the hafnocene dichloride as beige powder in a crude product yield of 700 mg (24%). The 1H-NMR spectrum of the crude product shows only one diastereomer.
Reaction SMILES: [CH:1](=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na].C(OC)(=O)[CH2:15][C:16]([CH3:18])=[O:17]>CO>[CH2:2]([CH:1]1[CH:7]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:18][C:16](=[O:17])[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=C1CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: CCCCCC1CC(=O)C=C2CCCC21
Yield: 57.5 %

Procedure:
The procedure of Example 1 is repeated with 98.5 g (0.59 mol) of hexylidene cyclopentanone, 1.61 g (0.072 g-atom) of sodium, 82 g (0.71 mol) of methyl acetoacetate, and 300 ml of methanol. The crude product is fractionated giving 70 g (bp 117°-123° C. at 0.5 mm) of 5-pentylbicyclo [4.3.0] non-1en-3-one having the structure: ##STR9##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCCCC2)CC1

Procedure:
Prepared in analogy to Example 1 from piperazine-1-carboxylic acid tert-butyl ester and cyclohexanone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][OH:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][C:7]1[C:8]([CH3:10])=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(Cl)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COCc1ccc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (266 mg of 60%, 6.66 mol) was suspended in tetrahydrofuran (14.8 mL) and cooled to 0° C. (6-Chloro-2-methylpyridin-3-yl)methanol (Example 421 Step 1) (350 mg, 2.22 mmol) was added and the mixture was stirred for 30 minutes at 0° C. Ethyl bromoacetate (0.25 mL, 2.22 mmol) was added and the solution was heated to 50° C. for 4 hours. The reaction mixture was then cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate three times. All the organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and purified via silica gel chromatography (0-100% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([S:12](Cl)(=O)=O)=[C:4]([CH:16]([CH3:18])[CH3:17])[CH:3]=1.BrC1C(C(CC)C)=CC(S(Cl)(=O)=O)=C(C(CC)C)C=1>>[Cl:1][C:2]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([SH:12])=[C:4]([CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)Cc1cc(S(=O)(=O)Cl)c(C(C)C)cc1Cl
Agent: CCC(C)c1cc(S(=O)(=O)Cl)c(C(C)CC)cc1Br
Product: CC(C)Cc1cc(S)c(C(C)C)cc1Cl

Procedure:
4-Chloro-2-isopropyl-5-isobutylbenzenethiol was prepared using the procedure of Example 2B except that 4-chloro-2-isopropyl-5-isobutylbenzenesulfonyl chloride was substituted for the 4-bromo-2,5-di-sec-butylbenzenesulfonyl chloride. The resulting product had a boiling point of 77°C at 0.1 mm Hg.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)c1csc(CN2CCCC2)n1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CN2CCCC2)n1
Yield: 55.7 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyrrolidin-1-ylmethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-pyrrolidin-1-ylmethyl-thiazole-4-carboxylic acid (0.244 g, 1.151 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The crude product was washed with water. Yield 55.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 1.72-1.76 (m, 4H), 2.57-2.61 (m, 4H), 3.95 (s, 2H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.41-4.50 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.09 (dd, 1H), 8.13 (s, 1H), 8.44 (d, 1H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@@H:8]([O:31][CH3:32])[C@@H:9]([N:13]([C:15](=[O:30])[C@H:16]([CH:27]([CH3:29])[CH3:28])[NH:17][C:18](=[O:26])[C@H:19]([CH:23]([CH3:25])[CH3:24])[N:20]([CH3:22])[CH3:21])[CH3:14])[CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][N:20]([CH3:21])[C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:13]([C@@H:9]([CH:10]([CH3:12])[CH3:11])[C@H:8]([O:31][CH3:32])[CH2:7][C:6]([OH:33])=[O:5])[CH3:14])=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H](CC(=O)O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Reaction time: 2 h
Yield: 148.9 %

Procedure:
To a solution of t-butyl-(3R,4S)-4-[N-(N,N-dimethyl-L-valyl-L-valyl)-N-methylamino]-3-methoxy-5-methylhexanoate (0.22 g, 0.433 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml). After stirring for 2 h, the reaction mixture was concentrated in vacuo. Reevaporation of the residue with toluene (5×10 ml) gave the deprotected product (0.268 g) which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-])=[C:6]2[CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:12][C:5]2=[N:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[C:6]2[CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:12][C:5]2=[N:4][CH:3]=1
Reactant: CC(=O)N1CCc2ncc(N)[n+]([O-])c2C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(=O)N1CCc2ncc(N)nc2C1

Procedure:
This intermediate was prepared analogous to Example 19 from 3-amino-6-acetyl-5,6,7,8-tetrahydro-pyrido[3,4-b]pyrazine-4-oxide by reduction with sodium dithionite.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[CH:7]=1
Reactant: Oc1cnc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Cl)ncc1=O
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 5-chloro-pyrazin-2-ol (100 mg, 0.76 mmol) in DMF (3 mL) was added K2CO3 (211 mg, 1.53 mmol) and CH3I (0.25 ml, 4 mmol) at room temperature. The mixture was stirred overnight, quenched by H2O, and extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by TLC to give 5-chloro-1-methyl-1H-pyrazin-2-one (70 mg, 64%). 1H NMR (CD3OD): δ3.52 (s, 3H), 7.78 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15][CH2:16][C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[CH:6][C:7]([F:14])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:4]1[C:5]([O:15][CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[CH:6][C:7]([F:14])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of methyl 5-acetyl-4-(adamantan-1-ylmethoxy)-2-fluorobenzoate (0.75 g, 2.10 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.441 g, 10.50 mmol) in water (4 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After adjusting the reaction mixture to pH 2 with 1 N hydrochloric acid, the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo yielded the title compound as a colorless oil (0.727 g, quant.), which was used without further purification: MS (ES−) m/z 345.3 (M−1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1.[NH2:19][CH2:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])=[CH:23][C:22]=1[F:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:24]2[CH:23]=[C:22]([F:39])[C:21]([CH2:20][NH:19][C:16]([C@:11]3([NH:10][C:8]([C:4]4[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=4)=[O:9])[CH2:15][CH2:14][O:13][CH2:12]3)=[O:18])=[N:26][CH:25]=2)=[C:29]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: O=C(N[C@@]1(C(=O)O)CCOC1)c1cn[nH]c(=O)c1
Reactant: NCc1ncc(Nc2ccc(Cl)cc2C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@]1(C(=O)NCc2ncc(Nc3ccc(Cl)cc3C(F)(F)F)cc2F)CCOC1)c1cn[nH]c(=O)c1

Procedure:
A solution of (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (144.7 mg, 0.40 mmol), (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine (127.9 mg, 0.40 mmol), TBTU (154 mg), triethylamine (0.112 mL) and DMF (1.0 mL) in 7 mL THF was stirred for 3 hours at ambient temperature. Then the mixture was evaporated down and the crude product thus obtained was purified by column chromatography (RP, column: YMC-Pack ODS-AQ, 5 μM).
Reaction SMILES: N([O-])=[O:2].[Na+].Cl.[CH3:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8]>O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([CH:6]=[O:2])=[O:8])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
adding sodium nitrite and hydrochloric acid to a solution of 4-hydroxyacetophenone in water to form 4-hydroxyphenylglyoxal;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([NH2:38])[CH:32]=1>>[NH2:38][C:33]1[CH:32]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:36]=[CH:35][C:34]=1[NH:37][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(C(F)(F)F)cc5N)cccc4c3)c2cc1OC
Yield: 79.1 %

Procedure:
The title compound (42.3 mg, 79% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-trifluoromethyl-o-phenylenediamine (21.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.72 (s, 2H, benzene-NH2), 6.92 (d, J=8.5 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.59-7.65 (m, 3H, Ar—H), 7.90-7.96 (m, 2H, Ar—H), 7.98 (s, 1H, Ar—H), 8.10 (d, J=8.3 Hz, 1H, Ar—H), 8.17 (d, J=7.3 Hz, 1H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.90 (s, 1H, benzene-NH). LC-MS (m/z) 535 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.