Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:5]([NH2:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cc(OCCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(OCCCCN2CCCCC2)cc1N
Yield: 97.8 %

Procedure:
758 mg of 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)-phenylamine in solution in 40 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 75 mg of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 670 mg of 4-fluoro-5-(4-piperidin-1-ylbutoxy)benzene-1,2-diamine are isolated in the form of a black oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.29 to 1.56 (m, 8H); 1.62 (m, 2H); from 2.20 to 2.32 (m, 6H); 3.82 (t, J=6.5 Hz, 2H); 4.27 (broad m, 4H); 6.32 (d, J=9.0 Hz, 1H); 6.34 (d, J=13.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([S-:17])#[N:16].[K+].BrBr>C(O)(=O)C>[NH2:16][C:15]1[S:17][C:13]2[CH:14]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of 4-benzylaniline (0.916 g, 5.00 mmol) and KSCN (0.97 g, 10.0 mmol, 2.0 eq) in 10 mL acetic acid was cooled at about 5° C., and was treated dropwise with a solution of bromine (0.258 mL, 5.00 mmol, 1.0 eq) in 2 mL acetic acid. The mixture was stirred at room temperature for about 1 hour. The precipitate was filtered off and washed with Et2O. The obtained solid was neutralized with saturated sodium carbonate solution, and a new precipitate was formed. It was filtered off, washed with water and MeOH, and dried under vacuum to give the desired compound 1.06 g (88%). LC/MS 241.2 (M+1); LC retention time 2.46 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][C:24]([CH3:27])=[N:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N:35]=[N+:36]=[N-:37])(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:10])[N:35]3[N:36]=[N:37][C:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[N:25][C:24]([CH3:27])=[N:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)=[C:14]3[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc(C#CCCCC(C)(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nnn3c2CCCC3(C)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
Boron trifluoride-diethyl ether complex (75.3 μL) was added to a mixture of 2-(3,4-dichlorophenyl)-7-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hept-6-yn-2-ol (88.0 mg), trimethylsilylazide (105 μL) and toluene (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min, at 70° C. for 15 min and at 110° C. for 6 hr, and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[CH2:35]([N:37]([CH2:45][CH3:46])[C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[OH:44])[CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:44][C@@H:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C@H:38]4[N:37]([CH2:45][CH3:46])[CH2:35][CH3:36])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CCN(CC)[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: CCN(CC)[C@@H]1CCCC[C@H]1Oc1ccc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OC)ccc23)cc1
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-trans-2-(diethylamino)cyclohexanol (Part A).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:4][C:3]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])(=[O:35])=[O:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])(=[O:34])=[O:35])=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCNCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.28 g, 2.03 mmol) in DCM (20 mL) was added TFA (3.10 mL, 40.5 mmol) at 0° C. The reaction mixture was stirred for 4 h at room temperature and removed the solvent in vacuo. DCM was poured into the residue, and neutralized with aq. Na2HCO3. The resulting solid was filtered and washed with MeOH and EtOAc to give N-(2-chloro-5-(4-(piperidin-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (954 mg, 89%) as a pale yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.84-2.00 (2H, m), 2.12-2.24 (2H, m), 3.04-3.18 (2H, m), 3.32-3.46 (2H, m), 4.38-4.52 (1H, m), 7.07 (1H, dt, J=2.0, 8.4 Hz), 7.22 (1H, dt, J=2.4, 10.0 Hz), 7.83-7.92 (1H, m), 8.04 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=2.4 Hz), 8.43 (2H, brs), 8.52 (1H, s), 8.59 (1H, d, J=2.4 Hz). m/z=532.2 [M+1]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]([C:27]([NH:29][C:30]3[S:31][C:32]([F:35])=[CH:33][N:34]=3)=[O:28])[CH2:14][C@H:15]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@@H:13]([CH2:14][C@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[C:27]([NH:29][C:30]3[S:31][C:32]([F:35])=[CH:33][N:34]=3)=[O:28])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Agent: Cl
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.17 h
Yield: 108.7 %

Procedure:
The (S)-tert-butyl 3-((R)-2-(4-(cyclopropylsulfonyl)phenyl)-3-((5-fluorothiazol-2-yl)amino)-3-oxopropyl)pyrrolidine-1-carboxylate (2.57 g, 4.91 mmol) obtained in Example 1 was dissolved in hydrochloric acid (4 M ethyl acetate solution, 10 mL), and the obtained mixture was then stirred for 10 minutes. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then dissolved in chloroform. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, was then dried over sodium sulfate, and was then concentrated in vacuo, so as to obtain (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (2.26 g, quant) in the form of a white solid.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](N(OC)C)=[O:21])=[N:12]1>C1COCC1>[C:20]([C:13]1[C:14](=[O:19])[C:15]([O:17][CH3:18])=[CH:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])[N:12]=1)(=[O:21])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccccc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 85.1 %

Procedure:
MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (3.20 g, 10.4 mmol) in THF (30 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution, saturated with NaCl, and extracted with AcOEt five times. The combined extracts were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (2.32 g, 85% yield) as pale yellow crystals: mp 154-156° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.91 (3H, s), 7.27-7.38 (2H, m), 7.45-7.53 (1H, m), 7.65 (1H, dt, J=1.5, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.62; H, 4.22; N, 10.79.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc2scc(C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 3,5-dimethylbenzothiophene (Intermediate 12) (5.0 g, 33.8 mmol) in CHCl3 (70 mL), chlorosulfonic acid (5.6 mL, 85 mmol) was added dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 h before it was poured into a mixture of ice and NaHCO3 and stirred vigorously for 5 min. The organic phase was immediately separated, dried with MgSO4 and concentrated yielding 3.5 g (40%) of the title compound.
Reaction SMILES: CC([N:5]([CH2:9][C:10](=[O:17])[NH:11][N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)C(=O)[O-])(C)C.[ClH:18]>>[ClH:18].[NH2:5][CH2:9][C:10]([NH:11][N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)=[O:17]
Reactant: CC(C)(C)N(CC(=O)Nn1cccc1)C(=O)[O-]
Agent: Cl
Product: NCC(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 1,1-dimethylethyl-[2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (5.67 g) was added 35 ml of a 3.7M ethereal hydrogen chloride solution. The reaction mixture was stirred at room temperature over a period of 5 hours. The colored powder obtained by suction filtration was purified by addition of a solution of the product in methanol/diethyl ether, collecting the precipitate and repeating this procedure several times until the greater part of the substance was dissolved in the mother liquors. The last precipitate was discarded and the combined mother liquors were again recrystallized from methanol/diethyl ether. This afforded 1.90 g (46%) of the product as a powder, m.p. 212°-215° C. (dec.).
Reaction SMILES: [CH2:1]1[CH2:9][N:8]2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])[CH2:7]2)[C@H:3]([OH:12])C1.C1(=O)O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](O)[C@@H]1[OH:15]>>[OH:12][CH:3]1[CH:4]2[N:8]([CH2:7][CH:6]([OH:10])[CH:5]2[OH:11])[CH2:9][CH:1]1[OH:15]
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](O)[C@@H]1O
Product: OC1CN2CC(O)C(O)C2C1O

Procedure:
The tetrahydroxypyrrolizidone (1) is an analogue of 1,8-diepiswainsonine. A similar analogue of swainsonine can be made by analogous methods starting with D-glycero-D-talo-heptono-1,4-lactone to produce the novel (1S), 2R, 6R, 7S)-1,2,6,7-tetrahydroxypyrrolizidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.P(Cl)(Cl)([Cl:25])=O>O>[Cl:25][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Temperature: 90 °C

Procedure:
2.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are suspended in approximately 40 ml of phosphorus oxychloride, and the suspension is heated at 90° C. for 2 hours. The reaction mixture is then introduced at from 35° to 45° C. into 250 ml of water. It is then diluted with a further 500 ml of water and the crystals which separate are filtered off and washed neutral with water to yield pure 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of slightly yellowish crystals, m.p. 143°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CN
Product: CNC(=O)c1sc(CCc2c(-c3ccc(F)cn3)noc2C)nc1C
Yield: 47 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using methylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (34 mg, 47%) which was obtained as an off white solid. MS: m/e=361.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].O.C(O)C>[C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Yield: 67.9 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(phenylsulphonylaminocarbonyl)-3-nitrobenzene (5 g, 16 mmol), 10% palladium on carbon (0.5 g, 10% (w/w)) in water (3 ml) and ethanol (100 ml), the title compound (3 g,67%) was afforded as a pale beige solid after recrystallisation from ethanol. mp 135°-138° C. 1H NMR (360 MHz, D6 -DMSO) δ 6.75-6.78 (1H, m), 6.96-6.98 (2H, m), 7.10 (1H, dd, J=8.0 and 8.0 Hz), 7.60-7.73 (3H, m), 7.97 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccnc(Oc2cccnc2)c1

Procedure:
4-Nitro-2-(pyridin-3-yloxy)pyridine-N-oxide (D44) (1 g, 4.3 mmol) in acetic acid (75 ml) was treated with iron powder (1.2 g, 21.4 mmol) at room temperature. After 2 h the mixture was concentrated under reduced pressure and partitioned between 2M aq NaOH (100 ml) and dichloromethane (4×100 ml). The combined extracts were dried and evaporated to a white crystalline solid (0.75 g, 93%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11](C(N)=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].BrBr.[OH2:28]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([NH:8][C:6]([O:5][CH3:1])=[O:28])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(C(N)=O)c2C1
Reactant: O
Agent: BrBr
Agent: [Na]
Solvent: CO
Product: COC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 84 %

Procedure:
2-t-Butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine-10-carboxamide (0.5 g, 1.53 mmol) was added to a solution of sodium (0.078 g, 3.37 mmol) in methanol (31 ml), and bromine (0.245 g, 1.53 mmol) was added dropwise thereto while maintaining the temperature at 25° C. or lower. After completion of the dropwise addition, the resulting mixture was heated under reflux for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by a silica gel chromatography (hexane-ethyl acetate=1 : 1) to obtain the desired compound (0.46 g, 1.28 mmol, 84%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:16]1[CH2:17][CH2:18][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:79]5[CH2:80][CH2:81][CH:76]([N:71]6[CH2:75][CH2:74][CH2:73][CH2:72]6)[CH2:77][CH2:78]5)=[O:33])=[CH:35][CH:36]=4)=[O:37])=[CH:21][CH:20]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 58.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (37 mg, 58% yield); MS (ESI) m/z=642.7
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(C)N2CCCCC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)N2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of methyl 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoate (283 mg, 1.1 mmol) in the mixture solution of tetrahydrofuran:methanol:water=3:1:1 (10 mL) was added lithium hydroxide (100 mg, 4.2 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue was added water (50 mL). The mixture was extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the product 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoic acid as pale solid (247 mg, 89%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.[CH3:15][O+:16]([CH3:18])C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2C(=O)[CH2:47][CH2:46][CH2:45][C:44]=2[OH:50])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2[C:44](=[O:50])[CH2:45][CH2:46][CH2:47][C:15]=2[O:16][CH3:18])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:40])([F:42])[F:41])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=C(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1

Procedure:
N,N-Diisopropylethylamine (450 μL, 2.59 mmol) and trimethyloxonium tetrafluoroborate (331 mg, 2.24 mmol) are added to a mixture of 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 44, 500 mg, 1.12 mmol) in dichloromethane (4.0 mL), and the mixture is stirred at room temperature for 20 min Dichloromethane (20 mL) is added, and the phases are separated. The organic layer is washed three times with water and concentrated under reduced pressure. Yield: 567 mg; ESI mass spectrum [M+H]+=462; Retention time HPLC: 1.09 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16]O)[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16][F:35])[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CN(C)C(=O)/N=c1\sc(CO)cn1-c1ccc2c(c1)OC(F)(F)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)/N=c1\sc(CF)cn1-c1ccc2c(c1)OC(F)(F)O2
Reaction time: 4 h

Procedure:
A solution of N′-[(2Z)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-(hydroxymethyl)-1,3-thiazol-2(3H)-ylidene]-N,N-dimethylurea (Example 87, 0.2 g, 0.56 mmol) in dry CH2Cl2 (10 mL) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.148 g, 0.67 mmol). After 4 hours at room temperature, the mixture was neutralized by dropwise addition of a saturated solution of sodium bicarbonate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica using CH2Cl2 as mobile phase. 1H NMR (CDCl3) δ ppm 3.00 (6H), 5.20 (1H), 5.38 (1H), 7.00 (1H), 7.30 (2H), 7.38 (1H); MS (ESI) 360 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([N:7]1[C:13](=[O:14])[CH:12]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][CH:26]=[CH2:27])=[C:19]([Cl:28])[CH:18]=2)[CH2:11][CH2:10][C:9](=[O:30])[N:8]1[CH3:31])[CH3:6])C.CO>[OH-].[Na+].O>[CH2:25]([O:24][C:20]1[C:19]([Cl:28])=[CH:18][C:17]([C:16]([NH:15][CH:12]2[C:13](=[O:14])[N:7]([CH:5]([CH3:6])[C:4]([OH:32])=[O:3])[N:8]([CH3:31])[C:9](=[O:30])[CH2:10][CH2:11]2)=[O:29])=[CH:22][C:21]=1[Cl:23])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(C)N(C(C)C(=O)OCC)C2=O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(C)N(C(C)C(=O)O)C2=O)cc1Cl
Yield: 99.7 %

Procedure:
2-[6-(4-Allyloxy-3,5-dichloro-benzoylamino)-2-methyl-3,7-dioxo-[1,2]diazepan-1-yl]-propionic acid ethyl ester (17) (216 mg, 0.44 mmol) was stirred in 1N NaOH (2 mL) and MeOH (2 mL) at room temperature for 45 min. The mixture was diluted with water (30 mL), extracted with dichloromethane three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to afford 201 mg (99% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.58-1.68 (m, 3H), 1.88-2.00 (m, 1H), 2.40-2.48 (m, 1H), 2.80-3.18 (m, 2H), 3.25-3.48 (d, 3H), 4.47-4.65 (m, 2.5H), 4.74-4.81 (m, 0.5H), 4.90-5.05 (m, 1H), 5.27-5.31 (d, 1H), 5.38-5.43 (d, 1H), 6.08-61.8 (m, 1H), 7.07-7.22 (m, 2H), 7.71 (d, 2H). Analytical HPLC: 5.85 min. LC-MS (ES+): m/e=458, 460 (M+H+).