Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:25][CH2:24][CH2:23][N:17]1[C:16](=[O:19])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]2=[N:18]1
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1n(CCO)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 110 °C

Procedure:
6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (825 mg) from Example 1 above was dissolved in DMA (10 mL), 2-bromoethanol (1.0 g) and potassium carbonate (235 mg) were added. Heated overnight at 110° C. Filtered, concentrated, and purified by chromatography (ethyl acetate/hexanes). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was obtained as white solid (830 mg). m/z (ESI)=340.0 (base peak, M+H+); 701.1 (2M+Na+). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg) was dissolved in dry DMF and the NaH suspension (12 mg, 60% in oil) was added, followed shortly by 2-chloro-5-trifluoromethylpyridine (54 mg). Concentrated and purified on silica using ethyl acetate/hexanes gradient to obtain compound 180 as a white solid (71 mg). m/z (ESI)=486.1 (base peak, M+H+); 508.1 (M+Na+); 993.2 (2M+Na+). 1H NMR (δ, CDCl3, 400 MHz) 8.75 (s, 2H); 7.98 (d, 1H); 7.53 (d, 2H); 7.40-7.30 (m, 3H); 7.18 (d, 1H); 4.90 (t, 2H); 4.49 (t, 2H). 19F NMR (δ, CDCl3, 376 MHz) −58.36 (s, 1F); −61.99 (s, 1F).
Reaction SMILES: C(OC1C=C([SH:15])C=CC=1)C1C=CC=CC=1.[CH:16]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)N)([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:21]=[C:22]([SH:15])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)([CH3:18])[CH3:17]
Reactant: Sc1cccc(OCc2ccccc2)c1
Reactant: COc1cc(N)cc(OC(C)C)c1
Product: COc1cc(S)cc(OC(C)C)c1

Procedure:
Prepared as described for 3-benzyloxy-benzenethiol SM28 starting from 3-isopropoxy-5-methoxyaniline. MS m/z: 199 [M+H]+
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:26][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:27]([O-:29])=[O:28])[C:22]([CH3:24])([CH3:25])[CH3:23])=[O:11]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (1.68 g, 7.77 mmol) was added to a solution of (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 6.47 mmol) and DMAP (1.18 g, 9.7 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred overnight at room temperature and then washed with saturated NaHCO3 solution (60 mL) and water (60 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.94 g, 88%, 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 8.23 (m, 1H, Ph-H), 7.90 (m, 1H, Ph-H), 7.31 (m, 1H, Ph-H), 6.56 and 6.51 (2 s, 1H, Ph-CH), 2.38 (m, 1H), 2.07-1.9 (m, 2H), 1.69 (m, 1H), 1.13, 1.11, 1.07, 1.04, 1.02, 0.87 (6 s, 9H, CH3×3), 0.96 (s, 9H, (CH3)3C).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=O)[CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].Cl.[NH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO>[OH:14][N:13]=[C:5]1[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]1([CH3:11])[CH3:1]
Reactant: NO
Reactant: COC(=O)C1CC(=O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(=NO)C1(C)C
Temperature: 11 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-oxocyclobutanecarboxylate (1.0 equiv.), hydroxylamine hydrochloride (1.4 equiv.) and sodium bicarbonate (2.5 equiv.) was suspended in MeOH (0.6 M) and stirred at 11° C. for 12 h. The solvent was removed under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to give the crude title product methyl 3-(hydroxyimino)-2,2-dimethyl-cyclobutanecarboxylate (92.7% yield) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.73 (s, 3H), 3.27 (dd, J=7.6 Hz, 18.4 Hz, 1H), 3.04 (q, J=9.2 Hz, 18 Hz 1H), 2.89 (t, J=7.2 Hz, 8.8 Hz, 1H), 1.57 (s, 1H), 1.40 (s, 2H), 1.28 (s, 1H), 1.19 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([OH:35])([CH3:34])[CH3:33])=[N:4][C:5]([N:9]2[CH2:17][C@@H:16]3[C@@:11]([C:27]4[S:31][N:30]=[CH:29][CH:28]=4)([N:12]=[C:13]([NH:18]C(=O)C4C=CC=CC=4)[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].N1C=CC=CC=1.[ClH:42].CON.Cl.O1CCOCC1>C(O)C.C(Cl)Cl>[ClH:42].[NH2:18][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:17][N:9]([C:5]3[N:4]=[C:3]([C:32]([OH:35])([CH3:34])[CH3:33])[C:2]([F:1])=[C:7]([CH3:8])[N:6]=3)[CH2:10][C@:11]2([C:27]2[S:31][N:30]=[CH:29][CH:28]=2)[N:12]=1
Reactant: Cc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccns3)C2)nc(C(C)(C)O)c1F
Agent: CON
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3ccns3)C2)nc(C(C)(C)O)c1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (33 mg, 0.064 mmol) is dissolved in ethanol (2 mL). To this solution is added pyridine (0.052 mL, 0.6 mmol) and O-methylhydroxylamine hydrochloride (55 mg, 0.6 mmol). The reaction is warmed to 70° C. for 4 hours. The reaction is cooled to room temperature and stirred overnight (˜16 hrs). The mixture is concentrated to give the crude product which is purified via silica gel chromatography using a 0-10% (7 N NH3 in MeOH)/DCM to give the pure freebase. The freebase is dissolved in DCM (2 mL) and treated with 4 M HCl in dioxane (0.3 mL, 1.2 mmol). The mixture is concentrated to give the title compound as a white solid (18 mg, 0.04 mmol). ES/MS (m/z): 409 (M+H). [α]D20=−6.0° (C=1.0, MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCNCC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.062 mMol) propionyl chloride, the title compound was prepared.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:14])=O.C(O)(=O)C>CO.O>[OH:14][N:12]=[C:15]1[CH:20]=[CH:19][C:18](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:17]=[CH:16]1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
60 g of KOH are dissolved in 300 ml of methanol and heated up to 55° C. To the solution are added 32.2 g (0.27 mol) of phenylacetonitrile followed by 30.8 g (0.25 mol) of nitrobenzene. The reaction mixture is stirred at 55° C. for 4 h. After cooling, 400 ml of water are added with stirring. The resulting solution is acidified by addition of 110 ml of acetic acid in 100 ml of water, leading to a yellow-orange precipitate. The mixture is then filtered, and the yellow solid is washed with a mixture of methanol and water. The crude product is dried in air, boiled with 150 ml of benzene for 15 min., cooled, filtered and dried under vacuum. 42.6 g (77%) of (4-hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are obtained in the form of a yellow solid, having a melting point (mp) of 159-163° C. (dec.). The structure is confirmed by the 1H-NMR spectrum (CDCl3), δ [ppm]: 6.75(Z)/6.89(E) (dd, 1H), 7.08(Z)/7.15(E) (dd, 1H), 7.25-7.53 (m, 7H), 9.56 (br s, 1H). 1H-NMR reveals that the product is a 50:50 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers. 1.2: (4-Diethoxyphosphoryloxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile 8 g (36 mmol) of (4-hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 6.8 g (39 mmol) of diethylphosphoryl chloride to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred for 1 h. The reaction mixture is poured into 100 ml of water, and extracted with ethyl acetate. The organic phase is washed with 0.1 N hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by flash chromatography on silica gel with ethyl acetate—hexane (1:1) as eluent. The product is a brown liquid. The structure is confirmed by the 1H-NMR spectrum (CDCl3); δ [ppm]: 1.37-1.44 (m, 6H), 4.23-4.36 (m, 4H), 6.84(Z)/6.97(E) (dd, 1H), 7.17(Z)/7.21(E) (dd, 1H), 7.26(E)/7.38(Z) (dd, 1H), 7.46-7.55 (m, 6H). 1H-NMR reveals that the product is a 67:33 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][C:23]=3[CH3:35])=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].CO.[OH-].[Na+].Cl>O>[CH3:3][C:2]([CH3:36])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][C:23]=3[CH3:35])=[O:20])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(OCC(=O)O)ccc1NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added ethyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetate (1.22 g, 2.45 mmol) and 20 mL of CH3OH. To this solution was added aqueous NaOH (10 mL of a 1N solution). The mixture was stirred at ambient temperature for 18 h. The mixture was neutralized with 10 mL of 1N HCl and diluted with H2O. The product was collected on a frit and washed with a little H2O. This material was dried in vacuo to give 0.953 g (83%) of 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetic acid as a white solid.
Reaction SMILES: C(OC(C1N(CC2C3C=C(F)C=CC=3SC=2)C2C(C=1C=O)=CC=CC=2)=O)C.C(OC(C1N(CC2C3C=C(F)C=CC=3SC=2)C2C(C=1CNC)=CC=CC=2)=O)C.C([O:58][C:59]([C:61]1[N:62]([CH2:77][C:78]2[C:79]3[CH:86]=[C:85]([F:87])[CH:84]=[CH:83][C:80]=3[S:81][CH:82]=2)[C:63]2[C:68]([C:69]=1[CH2:70][N:71]([C:73]([O:75][CH3:76])=[O:74])[CH3:72])=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])C>>[F:87][C:85]1[CH:84]=[CH:83][C:80]2[S:81][CH:82]=[C:78]([CH2:77][N:62]3[C:63]4[C:68](=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:69]([CH2:70][N:71]([C:73]([O:75][CH3:76])=[O:74])[CH3:72])=[C:61]3[C:59]([OH:60])=[O:58])[C:79]=2[CH:86]=1
Reactant: CCOC(=O)c1c(CN(C)C(=O)OC)c2ccccc2n1Cc1csc2ccc(F)cc12
Agent: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1csc2ccc(F)cc12
Agent: CCOC(=O)c1c(CNC)c2ccccc2n1Cc1csc2ccc(F)cc12
Product: COC(=O)N(C)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12

Procedure:
1-(5-Fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester (from Example 115.1.) was converted to 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester as described in Example 86.1. 117.2. 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester was converted to 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid as a white solid. MS: 425.5 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=1)[NH:6]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=1)[NH:6]2
Reactant: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Temperature: 25 °C
Yield: 107.3 %

Procedure:
Ethyl (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.99 g) was dissolved in a mixed solvent of tetrahydrofuran (12 mL)-methanol (12 mL), and the mixture was ice-cooled. Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.35 g) in water (5 mL)) was added to this solution, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (1.00 g, yield: 95%) as pale-yellow crystals. MS: 450 (MH+). melting point 269-270° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12]CC)C.C[O-].[Na+]>CO>[Cl:8][C:5]1[N:4]=[C:3]([O:12][CH3:10])[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: CCOCC
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 0 °C

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added 1 g 5-chloro-2,4-dichloro-pyrimidine, and 15 mL of diethyl ether. The mixture was cooled to 0° C. in an ice bath and then 1 equivalent of sodium methoxide in methanol (prepared from reacting 120 mg of sodium with 4 mL of methanol at room temperature) was slowly added. The reaction was stirred over night at room temperature and checked by LCMS. The white precipitate was filtered and the solid washed with cold methanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidine was obtained and this material was used without further purification.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][N:27]=1>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:30]([C:29]3[CH:33]=[CH:34][C:26]([NH2:25])=[N:27][CH:28]=3)[O:1][N:2]=2)[N:10]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Nc1ccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)cn1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 6-amino-nicotinic acid (0.07 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.055 g, 24%). MS (ISP) 453.1 [(M+H)+]; mp 205° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][N:8]([CH3:20])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O>C1(C)C=CC=CC=1>[CH3:7][N:8]([CH3:20])[C:9]([Cl:2])=[N:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CN(C)C(Cl)=Nc1ccc(Cl)c(Cl)c1
Yield: 100.2 %

Procedure:
10.4 g (0.05 mole) of phosphorus pentachloride and 11.6 g (0.05 mole) of N,N-dimethyl-N'-(3,4-dichlorophenyl)-urea in 74 ml of toluene are refluxed for 3 hours, and the volatile components are distilled off under 0.13 mbar to give 12.6 g of N,N-dimethyl-N'-(3,4-dichlorophenyl)-chloroformamidine in the form of an oil; nD25 : 1.6133.
Reaction SMILES: [CH:1]1([C:7]2([CH3:10])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-]=[N+]=[N-].[Na+]>>[CH:1]1([C@@:7]2([CH3:10])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C2CCCCC2)CO1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: C[C@]1(C2CCCCC2)CO1
Temperature: 24 °C
Reaction time: 2.5 h
Yield: 51.7 %

Procedure:
300 mg (2.14 mmol) of racemic 2-cyclohexyl-2-methyloxirane was dissolved in 40 mL Tris-SO4 buffer (200 mM, pH 7.5), followed by addition of purified enzyme (9 mg of halohydrin dehalogenase HheC in 280 μL buffer) and 69 mg (1.06 mmol) of NaN3. The reaction mixture was stirred at room temperature (24° C.) and monitored by gas chromatography (GC). The reaction was stopped after 2.5 h and extracted with 3×25 mL of ethylacetate. The combined organic phase was dried over Na2SO4 and solvent was evaporated. The crude product was chromatographed on a silica gel 60 H using pentane/CH2Cl2 (4:6) as eluent, which yielded pure (S)-2-cyclohexyl-2-methyloxirane (155 mg, 51% yield, e.e. 76%) and (R)-azido-2-cyclohexylpropanol-2-ol (163 mg, 41% yield, e.e.>99%). Optical purities were determined by GC using a Chiraldex G-TA column (30 m×0.25 mm×0.25 μm). The NMR data were identical with those of synthesized racemic reference compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[C:4]([CH3:20])[N:3]=1.[ClH:21]>O1CCOCC1>[ClH:21].[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:19])[CH2:10][NH2:11])[CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1cc(NC(C)CNC(=O)OC(C)(C)C)cc(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC(C)CN)cc(C)n1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(2,6-dimethylpyridin-4-ylamino)propylcarbamate (147 mg, 0.526 mmol) dissolved in 1,4-dioxane (1 ml) a 4N solution of HCl in dioxane (2 ml, 8.00 mmol) was added. Within a few minutes a precipitate started to form. The solvent was removed in a stream of nitrogen, to the residue was added diethylether and the mixture was allowed to stand at room temperature overnight. The solvent was filtered off, the residue was dried under reduced pressure to yield 135 mg of an off-white solid MS (ESI) m/z=180.0.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](Br)=[CH:17][CH:16]=1.NC(N)CCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:17][CH:16]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: CCCCCC(N)N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)c2ccccc12
Yield: 35 %

Procedure:
As depicted in Reaction 1, 3.3 g (20 mmol) of carbazole, 8.6 g (40 mmol) of 1,4-dibromonaphthalene, CuI, diaminohexane and K3PO4 were dissolved in dioxane and refluxed for 15 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give the title compound. The product was collected by filtration under reduced pressure and dried. Yield: 35%. MS (EI) (Calcd. for C22H14BrN: 371.03. Found: 371).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[C:24]([F:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)c(F)c3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.74 (m, 11H) 1.86-2.09 (m, 5H) 2.15 (s, 3H) 2.63-2.81 (m, 2H) 3.57-3.79 (m, 1H) 3.94-4.16 (m, 2H) 4.81 (t, J=8.1 Hz, 1H) 7.32-7.46 (m, 1H) 7.51 (t, J=8.6 Hz, 1H) 7.85 (br. s., 1H) 7.88 (dd, J=4.3, 2.3 Hz, 1H) 8.30 (s, 1H) 9.88 (s, 1H). [M+H] calc'd for C26H32F3N7O2, 532. found 532.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=O)C.O.[NH2:31][NH2:32]>CO>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)(=[O:3])[NH:31][NH2:32]
Reactant: NN
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of 2-ethoxycarbonyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 5) (1.0 g, 2.5 mmol) in methanol (50 ml) was added hydrazine hydrate (500 μl, 10.3 mmol) in methanol (20 ml). The reaction mixture was stirred at 60° C. for 16 h and then concentrated in vacuo. The residue was added ether and the solid isolated by filtration to yield 860 mg (88%) of the title compound. M.p. >250° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.O>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: ClCCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C1CCCc2c(O)cccc21
Solvent: O
Product: O=C1CCCc2c(OCCCN3CCN(c4ccc(Cl)cc4)CC3)cccc21
Yield: 70 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-chlorophenyl)-piperazine; yield 70.0% of theory; the hydrochloride, after recrystallization from 96% ethanol and drying in a vacuum desiccator, still contained 0.55 mol water; m.p. 189°-191°C;