Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:11]([CH2:50][OH:51])=[C:10]([Cl:52])[N:9]=1)[CH2:5][CH2:6][CH3:7].[CH3:53][S:54](Cl)(=[O:56])=[O:55].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:4]([C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]([CH2:50][O:51][S:54]([CH3:53])(=[O:56])=[O:55])=[C:10]([Cl:52])[N:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To a DCM (200 mL) solution of intermediate (11b) (13.6 g, 20.4 mmol), cooled to −78° C., was added methane sulfonyl chloride (6.3 mL, 81.6 mmol). The mixture was stirred at −78° C. for 15 minutes. A saturated NaHCO3 solution (100 mL) and EtOAc (500 mL) were added to the cooled mixture, which was then allowed to reach room temperature. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11c) as a yellow oil (15 g) which was used directly in the next step. MS m/z: [M+H+] calcd for C42H39ClN6O3S, 743.26; due to the reactive nature of intermediate (11c), only the methanol substituted product was observed upon running a mass spectrum of the sample when dissolved in methanol; methanol substituted product [M+H+]=679.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C>C1COCC1>[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:14]1
Reactant: CN(C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added N,N-dimethylpyrrolidin-3-amine (400 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, the residue was dissolved in dichloromethane and washed with 1 N HCl aq. and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (360 mg, 56%) as a purple solid: ESI MS m/z 207 [C11H18N4+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccc(OCCN2CCCC2)c2ncccc12
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c4ncccc34)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline (200 mg, 0.54 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (116 mg, 0.54 mmol).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][C@H:6]([CH3:17])[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][C@H:6]1[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:8][CH2:7]1
Reactant: C[C@@H](O)CCNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a stirred solution of thionyl chloride (2.9 g, 24.3 mmol) in acetonitrile (15 mL) is cooled to −45° C. is added a solution of tert-butyl [(3R)-3-hydroxybutyl]carbamate (1.8 g, 9.7 mmol) in acetonitrile (20 mL) by syringe over 10 min, keeping the internal temperature below −40° C. 4-Dimethylaminopyridine (119 mg, 0.97 mmol) is added followed by the slow addition of pyridine (3.9 mL, 48.6 mmol), keeping the temperature below −40° C. Ethyl acetate (50 mL) is added to the suspension and the mixture at −35° C. is filtered. The solid is washed with EtOAc and the filtrates are combined. Saturated Na2HPO4 solution (20 mL) is added into the filtrates and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4, dried (MgSO4) and concentrated to afford the title compound (2.3 g, 99%) which is used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[F:19])=[O:32])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-fluoro-2-isocyanato-4-trifluoromethyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 445 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.66 (s, 2H) 7.36-7.45 (m, 1H) 7.46-7.55 (m, 1H) 7.50 (d, J=8.73 Hz, 2H) 7.65 (d, J=8.42 Hz, 2H) 7.95 (s, 1H) 8.64 (dd, J=7.33, 2.03 Hz, 1H) 8.87 (s, 1H) 8.95 (d, J=2.81 Hz, 1H) 9.35 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)ccc1OC
Solvent: CCOCC
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
To a solution of 3-ethoxy-4-methoxybenzaldehyde (6.0 g, 33.3 mmol, 1.0 equiv; commercially available) in diethyl ether (50 mL) was added dropwise nitric acid 65% (4.12 mL, 5.81 g, 59.9 mmol, 1.8 equiv) over a period of 30 min at rt. After the addition was completed the reaction mixture was heated to reflux for 4 h. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 5.85 g (78%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.53 (t, J=7.0 Hz, 3H), 4.04 (s, 3H), 4.26 (q, J=7.0 Hz, 2H), 7.37 (s, 1H), 7.61 (s, 1H), 10.40 (s, 1H). 13C NMR (75 MHz, CDCl3): δ14.34, 56.68, 65.35, 107.31, 110.48, 125.52, 143.56, 152.54, 152.70, 187.60. MS (ISP): 225.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH3:12])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10]Cl.[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:10][CH2:9][NH:8][C:7]4[CH:6]=[N:5][N:4]([CH3:12])[C:3](=[O:13])[C:2]=4[Cl:1])[CH2:26][CH2:27]3)=[N:20][O:21][C:17]=2[CH:16]=1
Reactant: Cn1ncc(NCCCl)c(Cl)c1=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Reaction time: 24 h
Yield: 80.2 %

Procedure:
1.9 g (8.6 millimoles) of 4-chloro-5-(2-choroethylamino)-2-methyl-2H-pyridazine-3-one, 40 ml of acetonitrile, 2.07 g (9.4 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 2.36 g of potassium carbonate and 0.17 g potassium iodide are admixed. The reaction mixture is heated to boiling for 24 hours, filtered over a magnesium sulfate containing carbon bed and the organic phase is evaporated. The crude product is dissolved in ethyl acetate, washed with water, the organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product is recrystallized from ethyl acetate. Thus 2.8 g of the desired compound are obtained, yield 80.5%. Mp.: 145–147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCN)cc1Br
Reactant: CC(C)c1cnc(Cl)nc1
Product: COc1ccc(CCNc2ncc(C(C)C)cn2)cc1Br

Procedure:
Similarly prepared from 2-(3-bromo-4-methoxyphenyl)ethanamine and 2-chloro-5-isopropyl-pyrimidine (see below).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)([O-])=O.I[CH3:25].[H-].[Na+]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[1-(3-nitro-4-pyridyl)-4-piperidyl]carbamate (2100 mg, 6.514 mmol) (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) and iodomethane (4.623 g, 2.028 mL, 32.57 mmol) in DMF at 0° C. was added portionwise sodium hydride (312.7 mg, 7.817 mmol). The reaction was stirred at 0° C. for 1 h, and at room temperature for 1 h. The reaction was quenched by pouring the reaction mixture onto a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (2×50 mL). The combined organics was washed with brine (2×50 mL), dried and evaporated to leave an orange solid. To the crude solid dissolved in MeOH (50 mL) was added Pd/C (10%) (346 mg) and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction was filtered through celite and evaporated to leave tert-butyl (1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate as a yellow oil. (600 mg, 20%) MS (ES+-tBu) 251.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[C:47]([O:56]C(C)(C)C)(=[O:55])[C:48]1[C:49](=[CH:51][CH:52]=[CH:53][CH:54]=1)N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:54]2[CH:53]=[CH:52][CH:51]=[CH:49][C:48]=2[C:47]([OH:56])=[O:55])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccccc1C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl anthranilate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:37][C:38]([NH2:40])=[NH:39].[H-].[Na+]>O.CN(C)C=O>[CH3:29][O:28][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:39][C:38]([NH2:40])=[NH:37])[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[C:18]([CH3:27])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCNC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (40 mg), potassium carbonate (41 mg), and guanidine hydrochloride (28 mg). Sodium hydride (39 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with n-butanol. The n-butanol layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 17%).
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[N:7](C)[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].P([O-])(OC)O[CH3:17].CS(O)(=O)=O>>[F:1][CH:2]([F:14])[C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:6]([CH3:17])[N:7]=1
Reactant: COP([O-])OC
Reactant: CCOC(=O)c1cnn(C)c1C(F)F
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 170 °C
Reaction time: 7 h
Yield: 69.1 %

Procedure:
To 20.4 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) was added 11.3 g of dimethyl phosphite and 0.82 g of methane sulfonic acid. The mixture was heated to 170° C. and stirred for 7 hours. The solution was cooled and distilled to recover recycled trimethyl phosphate and 0.9 g of starting ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE). The remaining solution was added to 50 g of cold water. The solution was allowed to stir for 30 min. The precipitating solid was filtered and dried to give 14.1 g of product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:15]([F:34])=[CH:16][C:17]3[C:27](=[O:28])[C:26]([C:29]([O:31]CC)=[O:30])=[CH:25][N:19]4[CH:20]([CH3:24])[CH2:21][O:22][C:23]=2[C:18]=34)[CH2:9]1)=O)(C)(C)C.[ClH:35]>C(O)(=O)C>[ClH:35].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:15]([F:34])=[CH:16][C:17]3[C:27](=[O:28])[C:26]([C:29]([OH:31])=[O:30])=[CH:25][N:19]4[CH:20]([CH3:24])[CH2:21][O:22][C:23]=2[C:18]=34)[CH2:9]1
Reactant: CCOC(=O)c1cn2c3c(c(OC4CCN(C(=O)OC(C)(C)C)C4)c(F)cc3c1=O)OCC2C
Agent: Cl
Solvent: CC(=O)O
Product: CC1COc2c(OC3CCNC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
Ethyl 10-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3de][1,4]-benzoxazine-6-carboxylate (120 mg), 0.6 ml of concentrated hydrochloric acid and 2.6 ml of acetic acid were used. The ester was treated in a similar manner to Example 1-(2) and recrystallized from ethanol, whereby 50 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>N1C=CC=CC=1>[CH3:17][C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Compound 105 (250 mg, 0.93 mmol) was suspended in pyridine (0.5 mL). Decanoyl chloride (141 mg, 0.74 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (5 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (297 mg, 0.70 mmol, 95%) as a solid, mp 141-142° C.; 1H NMR (500 MHz, DMSO) δ 0.82 (3, t, J=7.0 Hz), 1.10-1.30 (12, m), 1.54-1.63 (2, m), 2.32 (2, t, J=7.0 Hz), 2.45 (3, s), 8.25 (2, d, J=8.0 Hz), 8.28 (2, d, J=8.0 Hz), 10.25 (1, s), 13.87 (1, s); 13C NMR (125 MHz, DMSO) δ 13.9, 16.0, 22.1, 24.9, 28.5, 28.6, 28.8, 28.9, 31.2, 36.4, 118.5, 126.8, 135.5, 142.7, 154.1, 167.6, 171.7; MS (LCQ, ESI+) Calculated for C19H29N4O3S2 425.2. found 425.1 (M+H)+. HRMS (FAB+, m/z) Calculated for C19H29N4O3S2 425.1681. found 425.1678 (M+H)+.
Reaction SMILES: C[O:2][NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].B(Br)(Br)Br.CO.C1OC1C>ClCCl>[OH:2][NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CONS(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Agent: CC1CO1
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(NO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.4 %

Procedure:
To a solution of methoxyphenylsulfonamide 13 (35.9 g, 70.8 mmol) in dichloromethane (3.5 L) at 0° C. was charged boron tribromide (1M in DCM, 40.1 mL, 425 mmol). The reaction content was allowed to warm to room temperature, stirred over two hours, and monitored by TLC assay (SiO2, 10% methanol in dichloromethane as eluent, dibenzyl product Rf=0.16, visualization by UV). To the contents at 0° C. was slowly charged propylene oxide (82 g, 1.42 mmol). Methanol (200 mL) was added and the reaction mixture was concentrated via rotary evaporator to afford a viscous oil. The crude product mixture was purified by silica gel column chromatography using 10% methanol in dichloromethane to afford the product 14 as a foam (22 g, 80% yield). 1H NMR (DMSO) δ 7.60 (d, 2H), 7.30-7.20 (m, 5H), 6.95 (d, 2H), 3.90-3.75 (m, 1H), 3.45-3.20 (m, 5H), 3.00-2.55 (m, 5H), 2.50-2.40 (m, 1H), 1.95-1.85 (m, 1H), 0.85 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=C(Cl)[C:25]([Cl:32])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(O)(C(F)(F)F)=O.C(O)(C)C>[Cl:32][C:25]1[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[CH2:12][CH2:13]2)=[C:27]([N+:28]([O-:30])=[O:29])[C:22]([NH2:21])=[N:23][CH:24]=1
Reactant: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
A solution of 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.126 g, 0.45 mmol) in dichloromethane (3.7 ml) and TFA (5 ml) was stirred at room temperature for 1.5 h then concentrated in vacuo, and the resulting residue was dried in vacuo. Part of this material (estimated 0.15 mmol) was dissolved in isopropanol (3 ml) and to this solution 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) was added followed by diisopropylethylamine (0.15 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (3 ml). The resulting yellow precipitate was collected by filtration, washed with isopropanol (2×3 ml), diethyl ether (2×3 ml), and dried (0.038 g, 73%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (s, 3H, isoxazole 5-CH3), 2.52 (br s 4H, piperazine N(CH2)2), 3.06 (br t, J=4.1 Hz, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2 isoxale), 6.21 (s, 1H, isoxazole 4-H), 6.96 (s, 2H, NH2), 8.06 (s, 1H, pyridine 6-H);
Reaction SMILES: [Cl-].[NH+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:8]#[N:9].[Na+].II.[OH-].[Na+]>O.CC(C)=O>[N:2]1[CH:7]=[CH:6][C:5]([C:4]2[CH:5]=[CH:6][N:9]=[CH:8][CH:3]=2)=[CH:4][CH:3]=1
Reactant: c1cc[nH+]cc1
Reactant: [C-]#N
Agent: II
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1cc(-c2ccncc2)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 22 parts of 1-[2-pyridyl)ethyl] pyridinium chloride (obtained from pyridine and 2-vinylpyridine as in Example 13) in 100 parts of a mixture of water-acetone (1:1 v/v) was added five parts sodium cyanide, and the mixture stirred 24 hours at 25° C. The resulting dark blue solution was oxidized with an alcoholic iodine solution until the blue color disappeared and 100 parts 40% sodium hydroxide added. Cleavage of the quat and workup as in Example 15 gave 4.9 parts 4,4'-bipyridine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH2:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]3)=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH:43][C:1](=[O:3])[CH3:2])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]3)=[CH:31][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)N1CCN(c2ccc(N)cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)c(COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)c1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
Acetyl chloride (4 μL, 0.057 mmol) was added under nitrogen to a solution of 4 (38 mg, 0.051 mmol) and N,N′-diisopropylethylamine (DIPEA; 8.7 μL, 0.062 mmol) in CHCl3 (2 mL). After 12 h, the reaction mixture was successively partitioned between CHCl3 and diluted NaHCO3, dried (Na2SO4) and evaporated. The residue was purified by column chromatography to give 25 mg (61.7%) of the title product 5 as a white powder: m/z=782 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.19-1.35 (m, 4H), 1.68-1.77 (m, 4H), 1.90 (m, 2H), 2.02 (s, 3H, COCH3), 2.18 (m, 2H), 2.33 (m, 2H), 2.50 (m, 1H), 2.75 (m, 2H), 2.92 (s, 3H, SO2CH3), 2.96 (m, 2H), 3.33 (m, 8H), 4.43 (s, 2H, CH2CONH), 5.22 (s, 2H, OCH2), 5.35 (m, 1H), 5.53 (m, 1H), 7.17-7.20 (m, 3H), 7.39-7.60 (m, 5H), 7.69-7.79 (m, 2H), 7.86 (broad s, 1H, NH), 8.33+8.56 (m, 1H, NH), 9.95 (s, 1H, NH).