Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C1C=CC=CC=1.[ClH:16]>CO.CCOCC>[ClH:16].[CH3:8][NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: c1ccc(CCNC2CCOCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNC1CCOCC1

Procedure:
The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11–4.00 (2H, m), 3.53–3.43 (2H, m), 3.37–3.27 (11H, m), 2.74 (3H, s), 2.11–2.03 (2H, m), 1.74–1.60 (2H, m).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.Cl>[OH-].[Na+]>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: CCOC(=O)c1cnn2c(S)cc(C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(S)n2ncc(C(=O)O)c2n1

Procedure:
Ethyl 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (J. Med. Chem. 1981, 24(5), 610-13) was heated in 1N aqueous sodium hydroxide solution until all has passed into solution. The reaction mixture was cooled and its pH was adjusted to 1 with aqueous hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from dimethylformamide. There was obtained 7-mercapto-5-methyl-pyrazolo[1,5-a] pyrimidine-3-carboxylic acid as a yellow powder having a of melting point of 161°-162° (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7]O)[CH2:4][C@H:3]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CS([Cl:21])(=O)=O.[CH2:22]([N:24](CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:21].[ClH:21].[C:22]([CH2:7][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1)#[N:24]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C[C@H](CO)C[C@H]1COc1cccnc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C[C@H](CC#N)C[C@H]1COc1cccnc1
Product: Cl

Procedure:
To a 386 mg (1.84 mmol) sample of 3-(trans-1-methyl-4-hydroxymethyl-2(S)-pyrrolidinylmethoxy)pyridine (from Example 48a above) dissolved in 12 mL of methylene chloride were added 262 μL (3.38 mmol) of methanesulfonyl chloride, 470 μL of triethylamine and a catalytic amount of DMAP, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with water, the product extracted from the mixture, the solvent removed, and the product purified by column chromatography on silica gel, eluting with 20:1 chloroform:methanol to afford 320 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:23]1[CH2:27][C@@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:23]3[CH2:27][C@@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@H](O)C2)c(I)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg, 0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). The RM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solvent was evaporated off under reduced pressure to give the crude product which was used directly without any further purification. UPLC-MS (Condition 3), tR=1.00 min, m/z=525.9/528.0 [M+H]+.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[S:48][C:47]([NH:49][C:50]([C:52]2[CH:56]=[CH:55][NH:54][N:53]=2)=[O:51])=[C:46]([C:57](=[O:59])[NH2:58])[CH:45]=1.[C:60]1([CH2:66][SH:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:66]([S:67][C:44]1[S:48][C:47]([NH:49][C:50]([C:52]2[CH:56]=[CH:55][NH:54][N:53]=2)=[O:51])=[C:46]([C:57](=[O:59])[NH2:58])[CH:45]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: SCc1ccccc1
Reactant: NC(=O)c1cc(Br)sc1NC(=O)c1cc[nH]n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(SCc2ccccc2)sc1NC(=O)c1cc[nH]n1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
A mixture of Pd2(dba)3 (20 mg, 0.022 mmol) and Xantphos (51 mg, 0.087 mmol) in 1,4-dioxane (5 mL) is degassed, put under N2 and sonicated. This mixture is then added to a degassed mixture of 1H-Pyrazole-3-carboxylic acid (5-bromo-3-carbamoyl-thiophen-2-yl)-amide (345 mg, 1.09 mmol), phenyl-methanethiol (135 μL, 1.15 mmol) and DIEA (380 μL, 2.18 mmol) in 1,4-dioxane (5 mL). Resulting mixture is stirred at 100° C. under N2. After 75 min, the reaction is diluted with DCM and washed with aqueous NaHCO3. The organic is then dried over MgSO4, filtered and evaporated to an oily residue. This residue is triturated in di-isopropylether, separated by filtration, the cake is dried, and the resulting the solid is used as such.
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:41][CH3:42])=[C:38]([Pb+3])[CH:39]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:41][CH3:42])=[C:36]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])[CH:35]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC12CCC(C(=O)CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.22 g, 1.22 mmol) (preparation described by H. Favre et al., Can. J. Chem. (1956), 34 1329-39) in dry chloroform (10 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is then added 4-dimethylaminopyridine (0.744 g, 6.15 mmol) and anhydrous toluene (3 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (0.673 g, 1.18 mmol) is added portionwise over 10 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (10 ml) is added, and the resulting biphasic mixture is filtered to remove any inorganic salts (washing with additional dichloromethane, 10 ml). The organic phase separated, and the aqueous phase is extracted again with dichloromethane (10 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give an orange gum. This crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.04 g, 9%) as a colourless gum.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH3:22])=O.O.[NH2:24][NH2:25]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Yield: 41.3 %

Procedure:
Prepared according to Method D Step A from [2-fluoro-3-(trifluoromethyl)phenyl](4-methoxy-2-methylphenyl)methanone (1.34 g, 4.90 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.620 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[C:14]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:33]([Cl:36])[CH2:34]Cl.O[N:38]1[C:42]2N=C[CH:45]=[CH:46][C:41]=2N=N1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[C:42]([NH:38][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:16][C:8]=2[O:7][CH2:6][C:5]2[CH:31]=[CH:32][C:2]([F:1])=[CH:3][CH:4]=2)[CH:41]=[CH:46][CH:45]=1
Reactant: ClCCCl
Reactant: On1nnc2cccnc21
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Nc3cccc(Cl)c3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluorobenzyl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)-4-(morpholine-4-carbonyl)benzoic acid (150 mg, 0.341 mmol) (may be prepared as described in description D68) in N,N-Dimethylformamide (DMF) (3 mL), was added EDC (98 mg, 0.512 mmol), 1-hydroxy-7-azabenzotriazole (55.8 mg, 0.410 mmol), DIPEA (0.119 mL, 0.683 mmol) 3-chloroaniline (0.054 mL, 0.512 mmol) and the mixture was stirred at room temperature overnight. The organics were evaporated and the residue was purified using the MDAP to give the title compound. Yield: 58 mg
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5](=[O:11])[O:6][C:7]([CH3:10])(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([NH2:24])[CH2:23][CH2:22]1.[CH:25](N(CC)C(C)C)(C)[CH3:26]>CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([N:24]2[CH2:2][CH2:3][N:4]([C:5]([O:6][CH2:7][CH2:10][CH2:25][CH3:26])=[O:11])[CH2:12][CH2:13]2)[CH2:23][CH2:22]1
Reactant: NC1(c2ccccn2)CC1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C2(c3ccccn3)CC2)CC1
Temperature: 100 °C
Yield: 17 %

Procedure:
To a stirred suspension of 0.32 g (1.3 mmol) of tert-butyl bis(2-chloroethyl)carbamate in 5 ml of N,N-diisopropylethylamine and 0.5 mL of anhydrous N,N-dimethylformamide was added 0.23 g (1.1 mmol) of 1-pyridin-2-ylcyclopropanamine, bis(hydrochloride) salt and the resulting mixture was heated to 100° C. for 15 h. The mixture was cooled to ambient temperature, quenched with water, and the aqueous phase extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 50% acetone/hexanes mixture to afford the title compound as yellow gum (0.055 g, 17% yield). 1H-NMR (500 MHz, CDCl3) δ 8.55 (d, J=4.7 Hz, 1H), 7.61 (td, J=7.7, 1.7 Hz, 1H), 7.33 (d, J=7.9, 4.6 Hz, 1H), 7.12 (dd, J=7.4, 4.9 Hz, 1H), 3.37-3.35 (m, 4H), 2.60-2.58 (m, 4H), 1.41 (s, 9H), 1.05-1.03 (m, 4H). LC-MS: m/z (ES) 304.5 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=2)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:20][N:19]=[C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:17]=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:43]([N:24]1[CH2:25][CH2:26][CH:21]([C:18]2[N:17]=[C:16]([NH:15][C:14]3[N:13]=[CH:12][C:11]([O:27][C:28]4[CH:29]=[CH:30][C:31]([CH:32]=[O:33])=[CH:34][CH:35]=4)=[CH:10][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[S:20][N:19]=2)[CH2:22][CH2:23]1)(=[O:45])[CH3:44]
Reactant: O=Cc1ccc(Oc2cnc(Nc3nc(C4CCNCC4)ns3)c(Sc3ccccc3Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
4-(5-(2-chlorophenylthio)-6-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)benzaldehyde (154 mg, 0.294 mmol) was dissolved in methylene chloride (3 mL) and triethylamine (81.9 μL, 0.588 mmol) and acetic anhydride (33.3 μL, 0.353 mmol) were added. After stirring for 20 minutes, the reaction was poured into saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was concentrated to afford 4-(6-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-chlorophenylthio)pyridin-3-yloxy)benzaldehyde (161 mg, 0.284 mmol, 96.8% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH3:17][S-:18].[Na+].O>CN(C)C=O>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([S:18][CH3:17])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium thiomethoxide (3.54 g, 50.5 mmol) and the reaction mixture was heated to 80° C. for 2 hrs. Cooled the reaction mixture, added water, stirred for 15 minutes and filtered white precipitate, dried to yield 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.60 g, 86% yield). LCMS (M+1=249)
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C(O)(=O)C.[CH2:12]([O:14][CH:15]1[O:19][C:18](=[O:20])[CH:17]=[CH:16]1)[CH3:13].N12CCCN=C1CCCCC2>ClCCl>[N:1]([CH:16]1[CH:15]([O:14][CH2:12][CH3:13])[O:19][C:18](=[O:20])[CH2:17]1)=[N+:2]=[N-:3]
Reactant: CCOC1C=CC(=O)O1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC1OC(=O)CC1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
This procedure was carried out in a manner similar to that described by D. J. Guerin, et al., Org. Lett (1999), 1, 1107-1109. To a solution of azidotrimethylsilane (25.8 mL, 0.32 mol) in dichloromethane (400 mL) at room temperature under nitrogen was added acetic acid (18.1 mL, 0.32 mol), and the reaction was stirred for 20 min. 5-Ethoxy-5H-furan-2-one (II, R1=Et) (8.10 g, 0.063 mol) was added dropwise, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 0.013 mol). The reaction was stirred for 24 h, washed with sodium bicarbonate, dried over sodium sulfate and evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes afforded 4-azido-5-ethoxy-dihydrofuran-2-one (7.85 g, 73% yield) as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[C:13]([C:15]([CH3:24])([CH3:23])[C:16]1[CH:21]=[CH:20]C(N)=C[CH:17]=1)#[N:14].NC1C=[CH:42][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=2)=[CH:28][CH:27]=1>ClCCl>[C:13]([C:15]([CH3:23])([CH3:24])[C:16]1[CH:17]=[CH:11][C:12]([NH:8][C:1]([NH:3][C:7]2[CH:6]=[CH:42][C:29]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=3)=[CH:28][CH:27]=2)=[O:2])=[CH:20][CH:21]=1)#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)cc1
Reaction time: 12 h

Procedure:
188 mg (1.16 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 175 mg (1.09 mmol) 4-(cyano-dimethyl-methyl)-phenylamine (Hicks, T. A., J. Med. Chem. 22 (1979) 1460-1464) in 4.0 ml dichloro-methane and stirred for 12 h. A solution of 284 mg (1.09 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (ethyl acetate). The obtained material was left overnight with dichloromethane, the precipitate filtered, washed with ether and dried. Yield: 180 mg (37%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 30.4 %

Procedure:
1.15-1.55 (3H, m), 3.19 (3H, s), 3.93-4.50 (4H, m), 6.49 (1H, d, J=12.0 Hz), 8.76-9.07 (2H, m). 2) By using 1.00 g of N-(5-fluoro-4-methylsulfonyl-2-nitrophenyl)glycine ethyl ester, 0.85 g of imidazole and 5 ml of DMF, 0.35 g (67%) of N-[5-(1H-imidazol-1-yl)-4-methylsulfonyl-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: COC([CH:5]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:8]2[CH:18]=[C:19]([Cl:23])[C:20]([Br:22])=[CH:21][C:7]=2[C:6]1=[O:24])=O>CC(O)=O.Cl.O>[CH:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH2:5][C:6](=[O:24])[C:7]2[CH:21]=[C:20]([Br:22])[C:19]([Cl:23])=[CH:18][C:8]1=2)=[O:13])([CH3:17])[CH3:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc2C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)OC(=O)N1CCCC(=O)c2cc(Br)c(Cl)cc21
Temperature: 100 °C
Yield: 80.3 %

Procedure:
A mixture of 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl ester (1.43 g, 3.42 mmol) in HOAc (30.0 ml), concentrated HCl (9.00 ml) and water (3.00 ml) was heated at 100° C. for 4 hours and then cooled down to room temperature overnight. The solvents were evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (100 ml) and saturated NaHCO3 (aq) (100 ml). The aqueous layer was extracted with more ethyl acetate (20.0 ml). The combined organics washed with brine (3×120 ml), dried over Na2SO4, filtered and concentrated. The material obtained was subjected to the conditions described in step 2 to provide 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (0.990 g, 80%) as white solid. MS (ES+): 360, 362 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O.CCCCCC>[Si:18]([O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of methyl (S)-(+)-3-hydroxy-2-methylpropionate (1.00 g; 8.47 mmol) and imidazole (1.15 g; 16.9 mmol) was dissolved in anhydrous dimethylformamide (10 ml), and t-butyl-dimethylchlorosilane (1.30 g; 8.62 mmol) was added thereto at room temperature, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, water (10 ml) and hexane (20 ml) were added, and after separation of the organic layer, the aqueous layer was extracted with hexane (10 ml) two times. The organic layers were combined together, washed with water (5 ml) three times and dried over anhydrous magnesium sulfate. Removal of the solvent by distillation under reduced pressure gave methyl (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropionate (1.91 g; yield, 97%) as a colorless oil. A portion of the oil (179 mg) was distilled by Kugelrohr® to give a purified product (176 mg) (bath temperature: 120° C./14 mmHg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[ClH:19].Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:22]1.N1CCCCC1>C(N(CC)CC)C.C1COCC1>[ClH:19].[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:22]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: C1CNCC(N2CCOCC2)C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCCC(N4CCOCC4)C3)s2)noc1C(F)(F)F
Yield: 65 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-piperidin-3-yl-morpholine, di-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. An additional 2 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCO3 solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (61 mg, 65%). LC/MS 4.66 min, [M+1]+ 430.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[N:10]([O-])=O.[Na+].[Sn](Cl)[Cl:15]>Cl.FC(F)(F)C(O)=O.O>[ClH:15].[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10]
Reactant: CSc1ccccc1N
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
2-Methylsulfanyl-phenylamine (23.6 g, 169.5 mmol) was suspended in conc. HCl (200 mL) and trifluoroacetic acid (130 mL), and cooled to 0° C. in an ice bath. Sodium nitrite (14.0 g, 203.4 mmol) was dissolved in water (45 mL) and added dropwise to the suspension over 45 min. After the addition, the reaction was stirred at 0° C. for 1 h. In a separate flask, tin(II) chloride (76 g, 338.4 mmol) was dissolved in conc. HCl (100 mL) and added slowly over 15 min to the reaction mixture. The resultant suspension was warmed to rt and stirred for 48 h. The reaction was filtered, washed with iso-propyl alcohol (15 mL), and dried to give 1-(2-methylsulfanyl-phenyl)hydrazine hydrochloride (30 g, 93%). 1H NMR (CD3OD, 300 MHz) δ 7.44 (d, 1H, J=7.7 Hz), 7.32–7.26 (m, 1H), 7.08–7.00 (m, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[CH:16](=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2)(=[O:18])[CH3:17]
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: CC=O
Solvent: c1ccccc1
Product: CC(=O)c1c2sc3ccccc3nc-2ccc1=O

Procedure:
A solution of 3H-phenothiazin-3-one (2 g) and acetaldehyde (32 ml) in benzene (240 ml) was irradiated with a 450 watt lamp for 2 days. The volatiles were removed under vacuum and the residue chromatographed on a silica gel column eluting with 25% EtOAc/hexane to afford the desired compound, m.p. 222° C.