Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)=[O:24])[CH:20]=[CH:19][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([Si:5]([CH3:10])([CH3:11])[O:6][CH2:7][CH2:8][NH:16][C:17]1[CH:22]=[C:21]([CH:23]([OH:24])[C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)[CH:20]=[CH:19][N:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(N)c2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (177.7 mg, 1.02 mmol), acetic acid (0.051 mL, 0.85 mmol) and N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (400 mg, 0.85 mmol) in DCM (3 mL) was stirred at RT for 1 hour. To the mixture was added sodium triacetoxyborohydride (360.8 mg, 1.7 mmol), stirred overnight. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by flash column to afford N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: N1(C(NC(=O)OC(C)(C)C)NC(=O)[O-])C=CC=N1.[O:19]=[C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH2:22][CH2:21]1.Cl.[N:35]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:36]1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:19]=[C:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27]([C@@H:36]2[CH2:40][CH2:41][CH2:42][N:35]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:33])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CCC(=O)CC1
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To prepare compound 2 of Scheme 7-1, tert-Butyl 4-oxocyclohexylcarbamate (9.0 g, 42.5 mmol) was treated with HCl (4N in 1,4-dioxane, 60 mL) at rt. After 4 h stirring, the reaction was concentrated to obtain the crude product (6.3 g), which was dissolved in anhydrous DMF (200 mL). N-Boc-L-Pro-OH (9.1 g, 42.3 mmol)), HATU (17.7 g, 46.6 mmol) and DIEA (22.8 mL, 131 mmol) were added at rt. After stirring overnight, the reaction was quenched by brine, extracted by ethyl acetate. The combined organic phases were washed with brine and H2O, dried with Na2SO4. After removal of the solvents, the crude product was purified by silica gel column chromatography (ethyl acetate) to afford (S)-tert-butyl 2-(4-oxocyclohexylcarbamoyl)pyrrolidine-1-carboxylate (7.5 g, 57% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]2[C:23](=O)[CH2:24][CH2:25][C:3]=12.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[C:17]1([C:14]2[N:13]=[CH:12][C:11]([C:10]3[CH:9]=[N:8][N:7]4[C:2]([NH2:1])=[C:3]5[CH2:25][CH2:24][CH:23]([NH:33][CH:30]6[CH2:31][CH2:32][O:27][CH2:28][CH2:29]6)[C:4]5=[N:5][C:6]=34)=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCOCC1
Reactant: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(NC1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-amino-3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-5-one (61.5 mg, 0.18 mmol), tetrahydro-2H-pyran-4-amine (100 uL), HOAc (100 uL) in EtOH (2 mL) was stirred at room temperature for 15 min. NaBH3CN (56.7 mg, 0.90 mmol) was added and the reaction was stirred overnight. Purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-N5-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine-5,8-diamine: LCMS tR=2.35 Min (10 min run, UV254nm), Mass calculated for, M+426.0, observed LC/MS m/z 427.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[Cl:31]>CN(C)C=O>[Cl:29][C:28]1[CH:27]=[C:26]([CH3:30])[CH:25]=[C:24]([Cl:31])[C:23]=1[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12]
Reactant: Cc1cc(Cl)c(OCCCCCCBr)c(Cl)c1
Reactant: O=C1NCCN1c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(OCCCCCCN2CCN(c3cccnc3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-pyridyl)-2-imidazolidinone (0.10 g, 0.63 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 38.2 mg, 0.96 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 2-[(6-Bromohexyl)oxy]-1,3-dichloro-5-methylbenzene (0.22 g, 0.64 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. 5 mL of a saturated aqueous NH4Cl solution and 10 mL of dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 5) as a white solid (0.36 g, 90%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[S:14]([CH2:17][CH2:11][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)([OH:16])(=[O:15])=[O:13]
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCCc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (4.76 g, 40 mmole) and 1,3-propane sultone (4.88 g, 40 mmole) in 50 mL reagent grade acetonitrile was heated under a nitrogen atmosphere and refluxed overnight. After cooling to room temperature, then to ice bath temperature, the resulting white solid was filtered and washed with cold acetonitrile. The yield was 8.1 g (84%), and the product had a melting point of greater than 200° C. Nuclear magnetic resonance (NMR) and elemental analysis showed the product to be consistent with the assigned structure. NMR (D2O): 7.45 (s, 4H), 2.8-4.0 (m, 8H), 2.2 (T, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)Cc1ccc(N)cc1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Temperature: 100 °C
Reaction time: 54 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (1.5 g, 9.46 mmol), (4-amino-2-methyl-phenyl)-acetic acid methyl ester (3.39 g 18.9 mmol, 2 equiv), and a 4 N solution of HCl in dioxane (6.9 mL, 28.0 mmol, 2.9 equiv) in MeOH/dioxane (30 mL; 1:1, v/v) is stirred for 54 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (CH2Cl2/MeOH, 1:0→98:2) provides the title compound: ES-MS: 302.1 [M+H]+; tR=4.79 min (System 1); Rf=0.43 (CH2Cl2).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]C>[Cu]Cl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: CSC
Agent: Cl[Cu]
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
40 g (0.22 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 0.44 g of copper(I) chloride are initially charged in 300 ml of dimethyl sulfide, and 26.1 g of n-butyl nitrite (0.23 mol) are added dropwise at 55-66° C. The mixture is then stirred at 60° C. for 1.5 hours. For work-up, the mixture is then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 38.7 g (85%) of a dark oil which solidifies after a while (content according to HPLC 94%). The product can be purified further by trituration in methyl tert-butyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: Cc1nc(NC(=O)c2cccc(C#N)c2)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-cyanobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 36% yield; m.p. 207-208° C.; 1H NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H) 7.67-7.58 (m, 1H), 7.36-7.32 (m, 5H), 5.99 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 377.2 (M+1).
Reaction SMILES: [O:1]1[C@:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[CH2:2]1.[NH3:21]>CO>[NH2:21][CH2:2][C@:3]1([OH:1])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:4]1
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CO4)C3)c2c1
Reactant: N
Solvent: CO
Product: N#Cc1ccc2ncn(C[C@H]3CCC[C@@](O)(CN)C3)c2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A suspension of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH (1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a microwave at 100° C. for 3 h. The reaction mixture was cooled to RT and blown down to dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile which was used without further purification. A solution of 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in three 20 mL microwave vials and heated with microwave at 160° C. for 3 h. The combined reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid was then filtered and washed with 2×10 mL of water. The solid was air-dried under house vacuum overnight. The compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-{[(5S,7S)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an off-white solid (856 mg, 97% yield). The aromatic region of the NMR spectra showed that the product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[Cl:48][C:49]1[CH:50]=[C:51]([C:56]2[CH:65]=[CH:64][C:59]3[NH:60][C:61]([NH2:63])=[N:62][C:58]=3[CH:57]=2)[CH:52]=[C:53]([F:55])[CH:54]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:48][C:49]1[CH:50]=[C:51]([C:56]2[CH:65]=[CH:64][C:59]3[NH:60][C:61]([NH:63][C:11]([C:9]4[N:10]=[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]5[CH:8]=4)=[O:13])=[N:62][C:58]=3[CH:57]=2)[CH:52]=[C:53]([F:55])[CH:54]=1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.46 g), and the mixture was heated at 80° C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on a 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2 M ammonia-methanol in DCM. 4.4 g of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 441.9. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (2H, br. s.) 9.08 (1H, s) 8.32-8.39 (1H, m) 7.82 (1H, s) 7.46-7.64 (6H, m).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(Cl)CCCCC1.[Mg].II.C1(=[O:28])CCC=C1.Cl.N.[NH4+].[Cl-]>O1CCCC1.O>[CH:1]1([CH:7]2[CH2:8][O:12][C:9](=[O:28])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(C2CCCCC2)C1
Reactant: O=C1C=CCC1
Agent: Cl
Agent: II
Agent: N
Solvent: ClC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(C2CCCCC2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
3-Cyclohexyl-cyclopentanone used hereinabove as starting material was prepared as indicated hereinafter: 16.6 g (0.148 Mole) of cyclohexyl chloride were added dropwise to 3.6 g (0.150 atome-g) of magnesium metal in a 250 ml vessel, under nitrogen atmosphere and in the presence of a iodine cristal. The reaction mixture was heated to reflux for 1 hour, then cooled to 0° and 1.42 g (0.074 Mole) of cuprous iodide were added thereto. After cooling the reaction mixture at -8°, 5.74 g (0.070 Mole) of cyclopent-2-ene-1-one in 40 ml of tetrahydrofurane were added dropwise. After having been stirred for 1 hour at -8°, the reaction mixture was poured onto 100 g of crushed ice, acidified with 15% HCl in water (pH 4-5) and finally neutralized by the addition of aqueous ammonia. After the addition of 10 g of NH4Cl the reaction mixture was extracted with ether (3×300 ml), washed with water (3×100 ml), dried over sodium sulfate and finally evaporated to afford 13.2 g of raw material. After purification by means of column chromatography (neutral Al2O3 --eluent:toluene) and subsequent distillation on a VIGREUX column, there were obtained 7.0 g (60% yield) of the desired product, b.p. 50°/0.005 Torr.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH:2]([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: CC1CNc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
1,2,3,4-Tetrahydro-3-methylquinoline (51 mg, 0.35 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.35 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 8.2 mg (12%) of 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.25, 2.2, 1H), 7.27 (d, J=2.3, 1H), 7.01 (d, J=8.3, 1H), 4.19 (s, 1H), 3.33 (m, 1H), 2.94 (dd, J=10.1, 10.1, 1H), 2.86 (ddd, J=13.8, 4.7, 1.7, 1H), 2.46 (dd, J=16.6, 10.0, 1H), 2.05 (m, 1H), 1.06 (d, J=6.7, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8](=[O:16])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:6]1)[CH3:4]>O>[CH2:3]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8](=[O:16])[C:7]([C:17]([OH:19])=[O:18])=[CH:6]1)[CH3:4]
Reactant: CCOC(=O)c1cn(CC)c2c(c1=O)C(=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c1CCCC2=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
Sodium hydroxide (1.6 g) was dissolved in 30 ml of water, and 2 g of ethyl 1-ethyl-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was added, and the mixture was stirred at 90° C. for 2 hours. The insoluble matter was removed, and the filtrate was adjusted to pH 1 with dilute hydrochloric acid under ice cooling. The crystals that precipitated were collected by filtration to afford 0.72 g of the captioned product. The product had a melting point of 212° to 214° C. (uncorrected). The infrared absorption spectrum (KBr tablet method) of the product had maximum absorptions at 3460, 2960, 1740, 1710, 1640 and 1495 cm-1. The nuclear magnetic resonance spectrum (CF3COOH, 60 Mc, TMS) had signals at δ1.70 (3H, t, J=7.5 Hz), 2.2-2.75 (2H, m), 2.8-3.2 (2H, m), 3.3-3.65 (2H, m), 4.64 (2H, q, J=7.5 Hz) and 9.30 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]#[C:14]Br>O.C(#N)C>[NH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2nc(N)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
300 mg (1.8 mmol) of methyl 3,4-diaminobenzoate was stirred in 5 ml of water. 0.5 ml of a solution of 5 M of cyanogen bromide in acetonitrile was added to the obtained mixture, and they were stirred at room temperature for 20 minutes. The mixture was filtered. Aqueous ammonia was added to the filtrate. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the title compound was obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:47]=1[NH:46][CH:45]=[C:44]2[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:40]=[CH:41][CH:42]=[C:43]4[C:47]=3[NH:46][CH:45]=[C:44]4[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
EDCI (189 mg) and HOBT (162 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (105 mg) in THF (2.5 mL), The mixture was stirred at room temperature for 0.5 hour, followed by addition of ethyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (200 mg) in THF (2.5 mL). The resulting mixture was stirred for 1 hour, followed by addition of TBAF (512 mg). The reaction vessel was sealed and stirred at 120° C. in the microwave for 1.5 hour. THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D36) (180 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.16 (3H, t), 1.40 (6H, d), 2.71 (2H, t), 3.03 (2H, t), 4.06 (2H, q), 5.46 (1H, m), 7.22 (1H, t), 7.28 (1H, d), 7.83 (1H, d), 7.94 (1H, d), 8.76 (1H, d), 9.06 (1H, d), 10.91 (1H, s);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]([N:13]=[C:14]([NH2:16])[NH2:15])#[N:12].[OH-].[K+]>COCCO.O>[NH2:12][C:11]1[N:13]=[C:14]([NH2:16])[N:15]=[C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[CH:4]=2)[N:7]=1
Reactant: CSc1cccc(C#N)c1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CSc1cccc(-c2nc(N)nc(N)n2)c1

Procedure:
4.0 g of m-methylthiobenzonitrile, 2.7 g of dicyanodiamide and 2.0 g of caustic potash are dissolved in 20 ml of methyl cellosolve, and the mixture is refluxed for 4 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from dioxane. Melting point: 229°-230° C.; Yield: 3.4 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.90) (0.392 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.409 g, 77%). MS (ISP) 531.3 [(M+H)+]; mp 156° C.