Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:31][CH2:30]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1cccc(C)c1CC1(N)CC1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1CC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
The compound is prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 52 mg (11%, trifluoroacetate); mass spectroscopy: [M+H]+=383.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].N1C=CC=CC=1.[CH2:15]([O:18][CH2:19][C@H:20]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21]O)[CH:16]=[CH2:17]>ClCCl>[CH2:15]([O:18][CH2:19][CH:20]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5])[CH:16]=[CH2:17]
Reactant: C=CCOC[C@@H](CO)OCc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOCC(COS(=O)(=O)C(F)(F)F)OCc1ccccc1
Yield: 101.1 %

Procedure:
Trifluoromethanesulfonic acid (5.95 ml, 36.3 mmol) is added dropwise at -30° C. to a mixture of dichloromethane (130 ml) and pyridine (3.19 g, 40.3 mmol). Compound 12 (8.95 g, 40.3 mmol) in dichloromethane (60 ml) is then added dropwise at -25° C. The mixture is allowed to come to room temperature and is concentrated in vacuo, and the residue is chromatographed (hexane/ethyl acetate 6:1). Compound 13a (13 g, 91%) is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl.[Cl:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:15]2[CH2:16][CH2:17][CH:13]([CH2:12][CH2:11][Cl:10])[CH2:14]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: ClCCC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCC1CCN(c2ccc(Cl)nn2)C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 8.9 parts of 3,6-dichloropyridazine, 8.6 parts of 3-(2-chloroethyl)pyrrolidine hydrochloride, 21.2 parts of sodium carbonate and 235 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 12.2 parts (99.1%) of 3-chloro-6-[3-(2-chloroethyl)-1-pyrrolidinyl]pyridazine as a residue (int. 94).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([C:27]#[N:28])=[C:6]([CH:26]=1)[O:7][C@@H:8]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)[CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C>Cl.O1CCOCC1>[ClH:1].[NH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]([O:7][C:6]1[CH:26]=[C:2]([Cl:1])[C:3]([F:29])=[CH:4][C:5]=1[C:27]#[N:28])[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1
Reactant: Cn1ccnc1[C@@H](CCCNC(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccnc1[C@@H](CCCN)Oc1cc(Cl)c(F)cc1C#N
Reaction time: 0.17 h
Yield: 157 %

Procedure:
The product of step (c) (0.33 g, 0.78 mmol) was dissolved in 4M hydrochloric acid in dioxan (10 ml) and stirred for 10 minutes. The solvent was removed in vacuo and the solid residue triturated with ethyl acetate. The white solid was filtered off and dried under high vacuum to give the title compound (0.22 g, 70%).
Reaction SMILES: [CH2:1]1[O:6]C(C2C=CC=CC=2)[O:4][CH2:3][CH:2]1[OH:13].[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[N:24]1[C:29]2[N:30]=[C:31](S(C)(=O)=O)[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C:28]=2[CH:27]=[CH:26][C:25]1=[O:46]>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[N:24]1[C:29]2[N:30]=[C:31]([O:13][CH:2]([CH2:3][OH:4])[CH2:1][OH:6])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C:28]=2[CH:27]=[CH:26][C:25]1=[O:46]
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(OC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 23 °C

Procedure:
1,3-O-Benzylideneglycerol (100 mg, 0.55 mmol) was dissolved in dry THF (5 mL) and stirred under Ar at 23° C. NaH (14 mg, 0.55 mmol) was added and the mixture stirred for 15 minutes at 23° C., and then cooled to −78°. The product of Example 48 (222 mg, 0.5 mmol) was added, and the mixture was allowed to slowly warm to 23°. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (2 mL), and H2O (0.5 mL) was added. The mixture was heated in an oil bath to 60° C. for three h, and then the solvents were removed in vacuo to give the crude product. The crude product was flash chromatographed twice on silica gel eluted with 20-50% EtOAc/CH2Cl2 to give the product as a white-amorphous solid. 104-107° C., LC MS m/z=458 (MH+) Retention time=1.88 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[CH:8][CH:7]=1.[CH3:28][C:29](C)([O-])C.[K+].ICC>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH2:28][CH3:29])[C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(NCc1cccc(-c2ccc(C3OCCO3)cc2)c1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCN(Cc1cccc(-c2ccc(C3OCCO3)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
600 mg (1.7 mmol) of N-(4′-[1,3]dioxolan-2-ylbiphenyl-3-ylmethyl)benzamide, 5 ml of THF and 206 mg (1.85 mmol) of potassium tert-butoxide are introduced into a three-necked flask under nitrogen. 300 μl 15 (3.7 mmol) of iodoethane are added dropwise. The reaction mixture is stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 400 mg (64%) of the desired product are obtained.
Reaction SMILES: C(O)C.[F:4][CH:5]([F:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N+:14]([O-])=O.[Cl-].[Ca+2].[Cl-]>O.[Zn]>[F:4][CH:5]([F:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH2:14]
Reactant: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1cccc(OC(F)F)c1N
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 400 ml of absolute ethanol, 50 ml of water, 72.6 g of zinc dust, 53.3 g of the 2-(difluoromethoxy)-6-methylnitrobenzene, (Example 3A), and a solution of 20.0 g of calcium chloride dissolved in 60 ml of water was refluxed for three hours, allowed to stand overnight, refluxed for an additional hour, and then an additional 43 g of zinc dust and a solution of 18 g of calcium chloride dissolved in 50 ml of water was added. Refluxing for an additional three hours was required to drive the reaction to completion. The reaction was vacuum filtered through Celite®, the filter cake rinsed with 300 ml of ethanol and the filtrate concentrated to a volume of 100 ml. The liquid was diluted with 300 ml of ethyl acetate, 80 ml of 10% sodium hydroxide solution and 100 ml of water. A precipitate formed which was removed by vacuum filtration through Celite. The filter cake was rinsed with 200 ml of ethyl acetate. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated to yield 25.8 g of the desired intermediate as a black oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[N:13]=[CH:12][C:11]=1[NH2:20])[CH2:2][CH2:3][CH3:4].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:21]1[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Cl
Reactant: CCCCOCCCNc1c(N)cnc2cccnc12
Product: CCCCOCCCn1c(CCCC)nc2cnc3cccnc3c21
Yield: 63.1 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of 1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as a colorless oil. A small portion was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide a pure sample as a white powder, m.p. 56.5-57.5° C. Analysis: Calculated for C20H28N4O: %C, 70.56; %H, 8.29; %N, 16.46; Found: %C, 70.48; %H, 8.25; %N, 16.61. 1H NMR (300 MHz, CDCl3): δ 9.32 (s, 1H), 8.90 (dd, J=4.3,1.6 Hz, 1H), 8.49 (dd, J=8.5,1.6 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, 1H), 4.94 (t, J=7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of the aldehyde 11 (50 g, 0.197 mol) in acetic anhydride (150 mL) was slowly added to a mixture of 70% nitric acid (900 mL) and acetic anhydride (200 mL) at 0° C. and was then left to stir for 2.5 hours at 0° C. The solution was then poured onto ice in a 5 L flask and the volume adjusted to 5 L with ice and water. The resulting light sensitive pale yellow precipitate was immediately filtered (the ester is slowly hydrolysed at room temperature in those conditions) and washed with cold water. The product 12 was used directly in the next step. TLC analysis (50/50 EtOAc/Pet Et) proved the product pure. 1H NMR (CDCl3) δ 10.4 (2H, s), 7.61 (1H, s), 7.4 (1H, s), 4.21 (2H, t, J=6.2 Hz), 4.00 (3H, s), 3.71 (2H, s), 2.58 (2H, t, J=7.1 Hz), 2.23 (2H, p, J=6.3 Hz); 13C NMR (CDCl3) δ 188.5, 172.8, 152.7, 151.0, 143.5, 124.7, 110.1, 108.2, 68.4, 56.4, 51.3, 29.7, 23.8; MS (ES+) m/z (relative intensity) 298 ([M+H]+, 100).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:35]1[CH:36]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH:14]=[CH2:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:32]=[C:33]([CH3:38])[N:34]=1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example M221) (175 mg, 0.316 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (104 mg, 76%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[S:10]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[CH:11]1>>[S:10]1[C:14]([C:15]([C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:16])=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1cncs1
Reactant: Ic1ncn2ccsc12
Product: O=C(c1cncs1)c1ncn2ccsc12
Yield: 75.6 %

Procedure:
7-(Thiazol-5-yl)carbonylimidazo[5,1-b]thiazole (187 mg) was prepared in the same manner as in step a) of Synthesis Example 3, except that 265 mg of 7-iodoimidazo[5,1-b]thiazole and 119 mg of thiazole-5-aldehyde were used as the starting compounds.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:30][CH3:31]
Reactant: CCI
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and ethyl iodide, white powdery N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: O.Cl.[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47](Cl)(=[O:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Zn].C(Cl)(Cl)Cl>[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47]([OH:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)O)c1
Reaction time: 0.5 h

Procedure:
87 ml of water and 18.2 ml (0.218 mol) of 12N-HCl were added to the solution of 87 ml of chloroform and 8.65 g (0.0121 mol) of the white solid containing 3,5-dihexadecyloxycarbonylbenzenesulfonyl chloride, and then 7.93 g of zinc was added thereto at 5° C. followed by stirring for 4 hours and 30 minutes. After the insoluble component was removed therefrom, the solution was extracted with 100 ml of chloroform, washed with saturated brine, and dried with Glauber's salt. After removing Glauber's salt, the solution was concentrated under reduced pressure, and the residue was recrystallized from hot hexane to obtain a colorless crystal of 3,5-dihexadecyloxycarbonylbenzenesulfinic acid. (Yield: 4.43 g, 48% (based on sodium 3,5-dimethyloxycarbonylbenzenesulfonate), m.p.: 63°-65° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1cccc2N1CCOCC1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(N3CCOCC3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3cccc(C#N)c3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide and 3-cyanophenylboronic acid. MS APCI (+) m/z 387 (M+1) detected; 1H-NMR (400 MHz, CDCl3) d 7.91 (m, 1H), 7.87-7.89 (m, 1H), 7.63-7.65 (m, 1H), 7.55 (t, 1H), 7.51 (br s, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 6.85 (s, 1H), 3.46 (br s, 4H), 2.90 (s, 2H), 1.62-1.72 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[C:24]4[CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:27]>C(Cl)Cl.N>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[C:24]4[CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(NCCN2CCCCC2)nc2ccc3c(c21)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCN2CCCCC2)[n+]([O-])c2ccc3c(c21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
H2O2 (70%, 0.27 mL, ca. 5.4 mmol) was added dropwise to a stirred solution of TFM (0.8 mL, 5.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 12 (170 mg, 0.5 mmol) and TFA (0.21 mL, 2.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 13 (89 mg, 50%) as a red solid: mp (MeOH/EtOAc) 138-141° C.; 1H NMR δ 8.12 (d, J=8.7 Hz, 1H, H-5), 7.70 (d, J=8.7 Hz, 1H, H-6), 7.44 (br s, 1H, NH), 3.70 (br t, J=7.6 Hz, 2H, H-9), 3.60-3.64 (m, 2H, CH2N), 3.04 (br t, J=7.7 Hz, 2H, H-7), 2.64 (br t, J=6.1 Hz, 2H, CH2N), 2.43-2.50 (m, 4H, 2×CH2), 2.21 (br p, J=7.7 Hz, 2H, H-8), 1.59-1.65 (m, 4H, 2×CH2), 1.42-1.48 (m, 2H, CH2); 13C NMR δ 149.1, 144.7, 138.6, 138.4, 132.7, 129.0, 115.7, 56.9, 54.4 (2), 38.1, 35.1, 32.9, 25.9 (2), 24.6, 24.3. Anal. calcd for C17H23N5O2.½H2O: C, 60.3; H, 7.2; N, 20.7. Found: C, 59.9; H, 7.0; N, 20.3%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:23]([NH:30][CH2:31][CH2:32][NH2:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Triethylamine (30.98 g, 306.1 mmol) was added to a solution of 2,4-dichloro-3-nitroquinoline (50.0 g, 204 mmol) in DMF (200 mL). A solution of N-Boc-ethylenediamine (32.7 g, 204 mmol) in DMF (100 mL) was then added in small portions. The reaction was stirred at room temperature, and then most of the DMF was removed under reduced pressure. Water (600 mL) was added to the residue, and the mixture was stirred for three hours. A solid formed and was isolated by filtration, washed with water, and dried under house vacuum to provide 71 g of tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate as a yellow solid. A portion of the material (15 g) was dissolved in dichloromethane (200 mL), and the resulting solution was washed with brine (2×100 mL) and deionized water (2×100 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and further dried on a vacuum pump for three days to provide 13.99 g of product.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:22]([NH:29][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)c2ccc(CNCc3ccccc3)cc2)CC1

Procedure:
To a solution of the product of Example 12 (150 mg) and benzylamine (0.062 mL) in DCM (5 mL) was added acetic acid (0.03 mL) and sodium triacetoxyborohydride (165 mg). After 16 h the reaction was treated with 1 N NaOH (20 mL) and extracted with DCM (3×20 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic ammonia-DCM) to give the title compound as an oil (150 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:19](C)=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([NH:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:12]([CH3:13])[N:11]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(N)ccc1COCC1CC1
Reactant: Cc1ccc(Cl)cc1S(=O)(=O)Cl
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.06 g) and 3-chloro-6-methyl-benzenesulfonyl chloride (0.072 g) as a light yellow solid (0.07 g). MS (ESI−): 364.9 ([M−H] )
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (471 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 μL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (407 mg, 92%) as a white solid.