Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][NH:17][C:18]([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:21]2[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[Cl:49])=[O:19])[CH:10]=1)(C)(C)C.ClC(Cl)C.FC(F)(F)C(O)=O>>[Cl:49][C:43]1[CH:44]=[C:45]([Cl:48])[CH:46]=[CH:47][C:42]=1[CH:21]1[CH:20]([C:18]([NH:17][O:16][CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:50])=[O:5])=[O:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)COc1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(OCC(=O)O)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized from ethyl acetate to obtain 184 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colorless crystal.
Reaction SMILES: [OH:1]O.[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH2:5]1.O=O>CO.O.[Pd]>[OH2:1].[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N+:9]([O-:1])([CH3:11])[CH3:10])[CH2:5]1
Reactant: OO
Reactant: CN(C)CC1CC(F)(F)C1
Agent: [Pd]
Agent: O=O
Solvent: O
Solvent: CO
Product: C[N+](C)([O-])CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30% Aqueous H2O2 (18 mL) was added dropwise to a stirred solution of 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol) prepared in Part B in methanol (100 mL) at 5 to 22° C. over 2 h. After stirring at RT for 20 h, additional 30% H2O2 (18 mL) was added. After 3 h, Pd black slurry (150 mg) in water (3 mL) was added to the stirred reaction mixture in small portions such that the temperature could be maintained between 5 to 25° C. with a cooling bath. The reaction mixture was stirred at RT for 1 h until the O2 evolution ceased. After filtration, the filtrate was concentrated in vacuo to give 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine oxide hydrate as a thick colorless oil (15 g, semisolid). 1H NMR (400 MHz, CD3OD) δ 3.47 (2H, d, J=5.29 Hz), 3.16 (6H, s), 2.75-2.92 (3H, m), 2.42-2.58 (2H, m).
Reaction SMILES: [Se].[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[O:14]1CCOCC1>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:14])=[N:10]2)=[CH:5][CH:4]=1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(Br)cc2n1
Agent: [Se]
Product: O=Cc1ccc2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Selenium dioxyde (1.6 g, 14 mmol, 1.3 eq) in suspension in dioxane (50 mL) was heated at 60° C. 7-bromoquinaldine (2.5 g, 11.2 mmol) was the introduced and the mixture was left to react at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered on celite, eluted with dioxane and concentrated under reduced pressure. The product was obtained pure as a white solid (3.3 g, >98%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:33]([C:32](=[CH:36][CH:37]4[CH2:39][CH2:38]4)[C:30]#[N:31])=[O:34])[CH2:25]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
To a mixture of (R)-5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropylacrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIPEA (102 mg, 0.78 mmol, 3 eq) in 10 mL DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq) and the reaction mixture was stirred for 4 h at RT under N2. The reaction mixture was purified by Pre-TLC to give the title compound (60 mg, 54% in yield). LCMS: m/z (505.0) (M+H)+ 1HNMR (400 MHz, CDCl3): δ 0.826˜0.837 (m, 2H), 1.147˜1.183 (m, 6H), 1.744˜2.210 (m, 5H), 4.661˜4.699 (m, 1H), 5.212˜5.226 (m, 2H), 6.499˜6.524 (m, 1H), 6.921˜7.367 (m, 10H) and 8.223 (S, 1H).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][S:22]C(=N)N)=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].OS([O-])(=O)=O.[K+]>O1CCOCC1.O>[C:2]([O:6][C:7]([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][SH:22])=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC(=N)N)c2CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a slurry of 3-tert-butoxycarbonyl-6-carbamimidoylthiomethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (1.582 g, 3.895 mmol) in anhydrous dioxane (16.3 mL) add at room temperature a solution of NaOH (0.17 g, 4.3 mmol) in water (0.48 mL). Heat the reaction mixture at 100° C. overnight. After cooling the reaction mixture to 12-15° C., add 1M aqueous KHSO4 (3.9 mL, 3.9 mol). Partition the mixture between water (25 mL) and hexane (50 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to an Analogix® column (150 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 20:80 EtOAc/hexane over 33 min; 20:80 EtOAc/hexane over 33 min; 35 mL/min) to afford the title compound (1.042 g, 82%) as a colorless oil. MS (ES+) m/z: 328.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C@@H:25]([CH2:30][OH:31])[C:26]([O:28]C)=[O:27])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.CC(C)C(NC(C1ON=C(C2C=CC(NC(NC3C=CC(C(F)(F)F)=CC=3)=O)=CC=2)C=1)=O)C(OC)=O.O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C@@H:25]([CH2:30][OH:31])[C:26]([OH:28])=[O:27])=[O:23])[O:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(-c2cc(C(=O)N[C@@H](CO)C(=O)O)on2)cc1)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
(S)-methyl 2-(3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxamido)-3-hydroxypropanoate (compound of Example 275, 200 mg, 0.452 mmol) was dissolved in THF and water in 2:1 ratio. Lithium hydroxide monohydrate (29 mg, 0.678 mmol) was added and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude compound was purified by washing with methanol to get 85 mg (44%) of the title compound. MS: ES (−): m/z 427 (M−1); ES (+): m/z 429(M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.377 (s, 1H), 8.885 (d, 1H), 8.701 (s, 1H), 8.178 (t, 1H), 7.892 (d, 2H), 7.692 (s, 1H), 7.641 (d, 2H), 7.289 (m, 1H), 7.188 (t, 1H), 7.066 (m, 1H), 4.492 (m, 1H), 3.868 (m, 2H), 3.554 (m, 1H), 3.087 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][OH:23])[CH3:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: CCOCCO
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: CCOCCOC(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
(2-Ethoxyethyl)-p-benzoylbenzoate was prepared from para-benzoyl benzoic acid chloride and 2-ethoxyethanol. The structure of the product was confirmed by the presence of carbonyl bands in the infrared spectrum at 1670 and 1730 cm-1. When added at 4% by weight loading to the solution described in Example 1, a cure rate of 15 ft./min./lamp was obtained. A sample in the same test solution was stable after three months storage following the procedure described in Example 5.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[CH2:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CC(C)(C)CO
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared in Example 193E, and neopentyl alcohol (43 mg, 0.49 mmol) were dissolved in DMF (2 mL) and NaH (25 mg, 0.62 mmol, 60% in mineral oil) was added with shaking and left overnight. The reaction mixture was carefully quenched with saturated NH4Cl solution, diluted with ethyl acetate and extracted with 1 N HCl, twice, then water, 3 times, and then dried over MgSO4. After filtration of the drying agent and concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the title compound (yield: 137 mg, 76%). mp 145-146° C. 1H NMR (300 MHz, DMSO-d6) δ 0.76 (s, 9H), 3.28 (s, 3H), 4.06 (s, 2H), 5.02 (q, J=9 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH3) m/z 419 (M+H)+, 436 (M+NH4)+. Anal. calc. for C18H21F3N2O4S: C, 51.67; H, 5.06; N, 6.69. Found: C, 51.47; H, 5.12; N, 6.48.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:22])[NH:15]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[N:24]([O-])=[O:25].[Na+]>O>[N:24]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:11]=1[CH2:12][CH2:13][C:14](=[O:22])[NH:15]2)=[O:25]
Reactant: O=N[O-]
Reactant: COc1ccc(-c2cn3ccccc3n2)c2c1NC(=O)CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2N=O)c2c1NC(=O)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a suspension of 5-(imidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (2.5 g) in 300 ml of water was added 1.71 ml of concentrated hydrochloric acid. The mixture was heated and the solution was cooled to 50° C. and 10 ml of aqueous solution having dissolved therein 0.65 g of sodium nitrite was added dropwise to the solution at 50° C. with stirring. After completion of addition, the reaction was continued for 2 hours and the reaction mixture was allowed to stand overnight at room temperature. Crystals which precipitated were collected by filtration, and recrystallized from methanol to give 1.9 g of 5-(3-nitrosoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12][C:9]=3[CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:22].[OH-].[K+].[ClH:25].[OH-].[Na+]>C(O)CO>[ClH:25].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:22]
Reactant: CCOC(=O)N1CCc2cc3c(cc2CC1)N(C)C(=O)CC3
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Product: CN1C(=O)CCc2cc3c(cc21)CCNCC3
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To 150 mg of ethyl 1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate were added 4 ml of ethylene glycol and 2 ml of a 40% aqueous potassium hydroxide solution, followed by heating at 120° C. and stirring for 18 hours. The reaction mixture was ice-cooled and the liquid was made acidic by the addition of concentrated hydrochloric acid, followed by stirring for an additional 1 hour. The reaction mixture was neutralized with a 1 M aqueous sodium hydroxide solution and then extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (elution solvent: chloroform-MeOH-aqueous ammonia). To a solution of the resulting residue in 2 ml of EtOAc was added 0.2 ml of a 4 M hydrogen chloride solution in EtOAc, followed by stirring. The solvent was concentrated under reduced pressure and the resulting solid was dissolved in 2 ml of EtOH under heating, followed by stirring at room temperature. The precipitated solid was collected by filtration to obtain 43.7 mg of 1-methyl-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one monohydrochloride as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:23]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: O=C(NCCCC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][N:7]1[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: ClCCCBr
Reactant: Cc1ccc2nn[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Cc1ccc2nnn(CCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
6-methyl-1H-benzotriazole (13.3 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method two for synthesis. The solution was separated and purified by HPLC to produce 7.2 g of 1-(3-chloropropyl)-6-methyl-1H-benzotriazole, with a yield of 34.3%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14]2)=[O:10].O>CN(C)C=O>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(C(=O)CBr)ccc2N1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cc2cc(C(=O)CN3CCCCC3)ccc2N1
Yield: 49.1 %

Procedure:
A solution of piperidine (0.39 ml, 3.9 mmole) and 5-(2-bromoacetyl)-2-indolinone (500 mg, 1.97 mmole) in N,N-dimethylformamide (15 ml) was stirred at room temperature 4 h then was poured into water (50 ml) and washed with dichloromethane (250 ml), the organic solution was washed with water several times and dried over sodium sulfate. After evaporation of the solvent the residue was chromatographed on siiica-gel using ethyl acetate as eluant to give 5-(2-piperidin-1-yl-acetyl)-2-indolinone (250 mg).
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[S:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH:2]([C:8]1[N:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[S:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C(O)c1csc(NS(C)(=O)=O)n1
Agent: CCOC(=O)C(O)c1csc(=NS(C)(=O)=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OC1CCCCO1)c1csc(NS(C)(=O)=O)n1

Procedure:
To a suspension of ethyl 2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (1.0 g.) and 3,4-dihydro-2H-pyran (0.36 g.) in ethyl acetate (5 ml.) was added p-toluene sulfonic acid (10 mg.) at room temperature with stirring, and then the suspension was stirred for 8 hours at the same temperature. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (10 ml.) and then the aqueous layer was separated. To the remaining organic layer was added diethyl ether (10 ml.) and then extracted with 5% sodium bicarbonate aqueous solution (20 ml.). Thus obtained aqueous extract was combined with the separated aqueous layer and adjusted to pH 4 with acetic acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, treated with activated charcoal and then dried over magnesium sulfate. The solvent was distilled off from the extract to give dark yellow oil of ethyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (1.0 g.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH3:14])[CH:13]=1.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[Cl-].[Na+]>CN(C)C=O>[CH3:14][C:12]1[CH:13]=[C:8]([CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[O:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:18]([O:27][CH3:28])=[O:26]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Oc1ccc([N+](=O)[O-])c(C)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Potassium carbonate (1.16 g, 8.39 mmol) was added to a solution of 5-fluoro-2-nitrotoluene (1.0 g, 6.45 mmol) and methyl salicylate (1.18 g, 7.74 mmol) in N,N-dimethylformamide (8 ml), and the resulting mixture was stirred at 140° C. for 1 hour. After the reaction, the reaction solution was cooled to 0° C. and a saturated aqueous sodium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer dried was concentrated and then purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain methyl 2-(3-methyl-4-nitrophenoxy)benzoate (1.88 g, 85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.O.[NH2:22][NH2:23]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:22][NH2:23])[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(Cl)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of the compound XVII (1.83 g, 6 mmol) in THF (10 mL) was added hydrazine monohydrate (0.84 mg, 17 mmol) and the mixture was stirred at room temperature over night. The mixture was concentrated to a volume of about 3 mL and diluted with ethyl acetate (50 mL) and water (10 mL). The organic phase was separated, rinsed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to afford the titled compound XXII (1.5 g, 83% yield, 92% purity): ESI/MS 319 (M+H), 317(M−H); 1H NMR (DMSO-d6): δ 10.40 (bs, 1H), 9.24 (bs, 1H), 8.08 (m, 1H), 7.42 (m, 2H), 4.43 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[CH3:34][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:34])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(C)O)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 535 mg, 1.2 mmol) was dissolved in THF (8 ml) cooled to −78° C. and charged with methylmagnesium bromide (3M, 0.786 ml, 2.357 mmol). The reaction was allowed to stir for 1 hr, eventually reaching 0° C. The reaction was slowly quenched with saturated ammonium chloride (3 mL) and partioned between EtOAc 2×10 mL, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was then loaded onto silica gel and purified by MPLC 0-25% EtOAc/hexanes to provide 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethanol (38B). MS: [M+H]+ m/z 470.
Reaction SMILES: Cl.Cl.NC1C(N)=CN=C([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)N=1.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([N+:32]([O-:34])=[O:33])=[C:27]([CH3:35])[CH:26]=1.N1CCC[C@@H](C(N2CCCC2)=O)C1>>[NH2:31][C:29]1[N:30]=[C:25]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:18])[CH2:12]2)[CH:26]=[C:27]([CH3:35])[C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: Cc1cc(Cl)nc(N)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([C@@H]1CCCNC1)N1CCCC1
Product: Cc1cc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc(N)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
(R)-(1-(6-Amino-4-methyl-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone was prepared using a method analogous to the one used for Intermediate 2, Step 1 but using 6-chloro-4-methyl-3-nitropyridin-2-amine and (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone as starting materials. The reaction mixture was run at 70° C. for 1 h. MS (ES+APCI) (M+H) 333.9; LCMS retention time 4.322 min (Method Z).