Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=4)=[N:18][CH:19]=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:26][C:27]3[CH:28]=[N:29][C:30]([O:34][CH3:35])=[C:31]([F:33])[CH:32]=3)=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[N:10]=1
Reactant: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of methyl 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.965 g, 1.542 mmol) and triflic acid (0.685 mL, 7.71 mmol), in 6 mL TFA was heated in a flask fitted with a reflux condenser and drying tube at 80° C. for 30 min. The dark red reaction was cooled and triflic acid (0.685 mL, 7.71 mmol) was added, and the reaction was reheated to 80° C. After 30 min, the reaction was judged complete. The reaction was cooled to 0° C., and ice was added, along with solid sodium bicarbonate, in portions, with rapid stirring. DCM was added. Upon complete quenching of acid, the thick mixture was extracted with 3×10% iPrOH/DCM, 2×10% iPrOH/EtOAc (EtOAc layers were washed 1× brine). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in diethyl ether, sonicated, and filtered, rinsing with 3× diethyl ether to give methyl 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.400 g, 1.038 mmol, 67.3% yield) as an orange solid. m/z (ESI, +ve ion) 386 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.37 (s, 1H), 9.26 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.31 (dd, J=12.4, 2.2 Hz, 1H), 8.01 (br. s., 1H), 7.84 (br. s., 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>>[CH2:1]([NH:5][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:16])=[O:17])[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)CN
Product: CC(C)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 78.8 %

Procedure:
The procedure described in Example 1A was performed using isobutylamine (0.396 g, 5.41 mmol) and 3-nitrobenzenesulfonyl chloride (1.0 g, 4.5 mmol) to give N-isobutyl-3-nitrobenzenesulfonamide (0.916 g, 78%). 1H NMR consistent with structure.
Reaction SMILES: [C:1]([N:4](C(OC(C)(C)C)=O)[N:5]1[CH2:10][C:9]([CH:11]=[O:12])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].[CH3:28][Mg+].[Br-]>C1COCC1>[C:1]([NH:4][N:5]1[CH2:10][C:9]([CH:11]([OH:12])[CH3:28])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)NN1CC(C(C)O)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (1.15 g, 3.00 mmol) [prepared according to Example 1, Step F] in THF (11.0 mL) at 0° C. was slowly added MeMgBr (3M solution in Et2O, 1.50 mL, 4.50 mmol) via syringe. The reaction mixture was allowed to warm to room temperature and stirred for another 20 h. The reaction mixture was quenched with sat NH4Cl solution and the aqueous layer extracted EtOAc. After washing of the combined organic layers with brine and drying (Na2SO4), the solvent was removed in vacuo to give the desired product as a viscous oil. LCMS (Method I) RT 1.19 min. [M+Na]+ 323.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dibromopyridine (200 mg, 0.844 mmol) in DMF (2 mL), was added sodium methanethiolate (65.1 mg, 0.929 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford Intermediate 165.1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[CH3:16][C:17]12[CH2:27][CH:21]3[CH2:22][C:23]([CH3:26])([CH2:25][C:19]([CH2:28][C:29](O)=[O:30])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[CH3:26][C:23]12[CH2:22][CH:21]3[CH2:27][C:17]([CH3:16])([CH2:18][C:19]([CH2:28][C:29]([NH:1][N:2]4[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:3]4=[O:15])=[O:30])([CH2:20]3)[CH2:25]1)[CH2:24]2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Reactant: CC12CC3CC(C)(C1)CC(CC(=O)O)(C3)C2
Product: CC(C)c1nn(NC(=O)CC23CC4CC(C)(CC(C)(C4)C2)C3)c(=O)c2ccccc12

Procedure:
The product from Example 1B and 2-(3,5-dimethyl-1-adamantyl)acetic acid were processed using the method described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.81 (s, 6H) 0.98-1.20 (m, 2H) 1.20-1.42 (m, 14H) 1.52 (s, 2H) 1.98-2.14 (m, 3H) 3.49-3.73 (m, 1H) 7.89 (t, J=7.48 Hz, 1H) 7.95-8.04 (m, 1H) 8.11 (d, J=8.24 Hz, 1H) 8.34 (d, J=6.71 Hz, 1H) 11.12 (s, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]([C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:24])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[N+:1]([C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:24])=[C:14]([C:12]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:13])[CH:23]=1)([O-:4])=[O:2]
Reactant: O=C(Oc1ccccc1)c1ccc2ccccc2c1O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])c2ccccc2c1O
Reaction time: 0.5 h
Yield: 62 %

Procedure:
12 ml of fuming nitric acid (d=1.5) was added dropwise to a solution of 53 g of 2-phenoxycarbonyl-1-naphthol dissolved in 200 ml of chloroform was added dropwise 12 cc of fuming nitric acid (d=1.5) at 10° C. to 30° C. After 30 minutes, the precipitated crystals were filtered, washed well with cooled chloroform to obtain the desired product at a yield of 62%. The product had m.p. of 157° C., and was confirmed by NMR, Mass spectra.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCOCC1.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].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:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Brc1cncc(N2CCOCC2)c1
Yield: 64.8 %

Procedure:
To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd2(dba)3 (195 mg, 0.21 mmol). The reaction was microwaved at 90° C. for 4 h. The reaction was poured into a mixture of CHC13/H20; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane→1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found C9H11BrN2O m/z 244 (M+H).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][S:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([O:16]C)=[O:15])=[N:13][C:6]=2[NH:5]1>O1CCOCC1.O>[O:3]=[C:4]1[CH2:9][S:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[N:13][C:6]=2[NH:5]1
Reactant: COC(=O)c1ccc2c(n1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CSc2ccc(C(=O)O)nc2N1
Reaction time: 8 h
Yield: 86 %

Procedure:
0.5 M NaOH solution (8 mL, 4 mmole) was added dropwise over 2 hr to a solution of methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg, 3.52 mmole) in dioxane (120 mL) and water (30 mL). The reaction was stirred overnight then was concentrated to about 3 mL. Water (5 mL) was added and the pH was adjusted to 4 with 2 M HCl. The precipitated solid was collected, washed with a small volume of water and dried under vacuum to give the title compound (636 mg, 86%) as a solid: MS (APCI−) m/e 209 (M−H)−, 165 (M-COOH)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH:37]([N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH:37]([CH3:39])[CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 703.4 [(M+H)+]
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][NH:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:3].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]([CH2:17][C:18]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)c1ccccc1
Reaction time: 96 h

Procedure:
To a solution of 0.48 g of the product of Example 6 and excess triethylamine in ethyl acetate at room temperature was added 0.16 mL benzoyl chloride all at once. The reaction mixture was allowed to sit 4 days at room temperature. The solution was then diluted with ethyl acetate and washed with dilute HCl, NaHCO3, and NaCl solutions, dried over MgSO4, filtered, and concentrated to an oil which was crystallized from diethyl ether. The white solid was collected by filtration. 0.48 g (61%). NMR (CDCl3) δ 1.12 (12H, d), δ 1.6-2.15 (8H, m), δ 2.99 (2H, m), δ 3.27 (2H, bs), δ 3.80 (2H, bs), δ 6.20 (1H, bs) δ 7.04-7.42 (13H, m). IR (KBr) 3269, 2963, 2869, 1696, 1600, 1520, 1461, 1254, 1222, 703 cm-1.
Reaction SMILES: [O:1]1[C@@:15]23[C@:6]4([CH2:18][CH2:17][NH:16][C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:19][CH3:20])=[CH:8][C:7]4=2)[CH2:5][CH2:4][CH2:3][CH:2]13.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:1][C@:15]12[C@@H:14]3[NH:16][CH2:17][CH2:18][C@:6]1([C:7]1[CH:8]=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][C:12]=1[CH2:13]3)[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: COc1ccc2c(c1)[C@@]13CCCC4O[C@@]41[C@@H](C2)NCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3

Procedure:
A solution of 800 mg. of the amine-epoxide (XX) in 10 ml. of tetrahydrofuran was added dropwise at room temperature, to a suspension of 50 mg. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran. After the addition had been completed, the reaction mixture was stirred and refluxed during fifteen minutes. Work up as usual yielded 700 mg. of an oil which was dissolved in ether and the resulting solution was filtered through a celitecharcoal mixture. The filtrate was treated with a saturated solution of hydrochloric acid in ether to yield 720 mg. of a white hydrochloride salt which after recrystallization from methanol melted at 243°-44° C.(dec.). The IR and NMR were consistent with the structure.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][C:24]([C:26]([NH2:33])([CH3:32])[CH2:27][CH:28]2[CH2:31][O:30][CH2:29]2)=[N:23][N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:33][C:26]([C:24]3[O:25][C:21]([CH3:20])=[N:22][N:23]=3)([CH3:32])[CH2:27][CH:28]3[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: Cc1nnc(C(C)(N)CC2COC2)o1
Product: Cc1nnc(C(C)(CC2COC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(oxetan-3-yl)propan-2-amine (example 190c) as starting materials and isolated (36 mg, 22%); MS (ESI, m/z): 441.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18]CC)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccnc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cc(C(=O)O)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of ethyl 2-(N-(tert-butoxycarbonyl)methylsulfonamido)isonicotinate (0.920 g, 2.67 mmol) in THF (15 ml), aqueous 1M LiOH (2.94 ml, 2.94 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and acidified with aqueous 2N HCl. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the solid residue was purified by trituration with iPr2O affording after filtration 2-(N-(tert-butoxycarbonyl)methylsulfonamido) isonicotinic acid as a white solid (0.625 g, 1.976 mmol, 74.0% yield, MS/ESI+ 339.2 [MNa]+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][N:3]=1.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:9]1([CH2:8][N:7]([C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)[C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1nnc(NCc2ccccc2)s1
Solvent: c1ccncc1
Product: Cc1nnc(N(Cc2ccccc2)C(=O)Cc2ccccc2)s1

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-benzylamine (15 g, 0.073 mole) in pyridine (200 ml) was refluxed with phenylacetyl chloride for 6 hours. The pyridine was removed under educed pressure and the residue treated with water and extracted with ether. The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ethanol to give the title compound, m.p. 128° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[CH:15]=[C:16]([C:33]([NH:35][C:36]2[CH:40]=[CH:39][N:38](C(OC(C)(C)C)=O)[N:37]=2)=[O:34])[CH:17]=[C:18]([O:20][C:21]2[CH:32]=[CH:31][C:24]3[C:25](=[O:30])[N:26]([CH3:29])[CH2:27][O:28][C:23]=3[CH:22]=2)[CH:19]=1)[CH2:10][O:11][CH3:12]>C(Cl)Cl>[CH3:8][C@H:9]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([O:20][C:21]2[CH:32]=[CH:31][C:24]3[C:25](=[O:30])[N:26]([CH3:29])[CH2:27][O:28][C:23]=3[CH:22]=2)[CH:19]=1)[C:33]([NH:35][C:36]1[CH:40]=[CH:39][NH:38][N:37]=1)=[O:34])[CH2:10][O:11][CH3:12]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 1,1-dimethylethyl 3-[({3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate (190 mg, 0.34 mmol) in DCM (12 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo and DCM (20 mL) added and the mixture washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a white solid (54 mg). 1H NMR δ (CDCl3): 1.32 (d, 3H), 3.09 (s, 3H), 3.40 (s, 3H), 3.47-3.63 (m, 2H), 4.56-4.63 (m, 1H), 5.16 (s, 2H), 6.52 (d, 1H), 6.71-6.74 (m, 1H), 6.81 (t, 1H), 6.85 (s, 1H), 7.18 (s, 1H), 7.37 (s, 1H), 7.49 (s, 1H), 7.92 (d, 1H), 9.46 (s, 1H), 9.46 (s, 1H); m/z 453 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl piperidine-2-carboxylate (15 g, 95 mmol), triethylamine (27 ml, 191 mmol) and 4-dimethylaminopyridine (0.58 g, 4.8 mmol) in dichloromethane (100 ml) at 0° C. is added a solution of benzyl chloridocarbonate (17 g, 100 mmol) dropwise. The reaction is allowed to warm slowly to room temperature. It is stirred at room temperature overnight (16 h), then allowed to stand for 2 days. The crude product is extracted with dichloromethane, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 (300 g) with cyclohexane/ethyl acetate as eluent to afford a pale yellow oil.
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N+:13]([O-])=[CH:12][C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[NH4+:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:23])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.20 g, 4.23 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated ammonium hydroxide solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (849 mg, 4.45 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then diluted with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-25% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate gave (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (479 mg) as amber crystals, mp 249.0-250.0° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.[CH3:12][NH:13][NH2:14].C(O)(=O)C(O)=O>CC(O)C.O>[CH3:12][N:13]1[C:5](=[O:7])[N:4]([NH:3][C:2](=[O:6])[CH3:1])[CH2:8][C:9]([CH3:10])=[N:14]1
Reactant: CNN
Reactant: CC(=O)Cn1nc(C)oc1=O
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NN1CC(C)=NN(C)C1=O
Yield: 53.6 %

Procedure:
To a solution of 5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (1.518 g, 9.72 mmol) in a mixture of 2-propanol (8.8 mL) and water (0.22 mL) is added methyl hydrazine (0.79 mL, 14.6 mmol). The reaction mixture is heated to reflux under N2 for 4 h, and then a solution of oxalic acid (0.273 g, 2.92 mmol) in 2-propanol (4 mL) is added. The resulting precipitate is removed by filtration. The filtrate is concentrated in vacuo and the residue dissolved in 2-propanol (25 mL). The solution is chilled and Et2O is added. The precipitate is collected by filtration and dried to afford N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (0.96 g, 54%) as a crystalline solid. MS: 185 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 4.18 (s, 2H), 3.28 (s, 3H), 2.02 (s, 3H), 1.95 (s, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21](OCC)=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([NH:7][C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing solution of 101.4 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate in 640 parts of dry benzene is added dropwise a solution of 172 parts of a sodium dihydro-bis(2-methoxyethoxy)aluminate 70% in benzene, in 160 parts of dry benzene. Upon completion, stirring is continued for 2 h. 30 at 80° C. The reaction mixture is cooled, poured onto ice-water, alkalized with sodium hydroxide solution and the product is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol and 1,1'-oxybisethane. The salt is filtered off, boiled in 2-propanol and after cooling, the product is filtered off. It is boiled once more in acetonitrile and the salt is filtered off again after cooling. The free base is liberated in the conventional manner. After extraction with 1,1'-oxybisethane, the latter is washed with water, dried and evaporated, yielding 56.6 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol as an oily residue.