Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>CN(C)C=O>[NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: CN(C)C(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(N)=C(C#N)C(N)=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 5.4 g of 3-amino-2-cyano-3-(dimethylamino)propenenitrile and 4.0 g of triethylamine in 25 ml of dimethylformamide at 50° were added 11.6 g of aqueous hydrogen sulfide. Upon complete addition of hydrogen sulfide, the reaction mixture was heated at 65° for 1 hour. Since comparison by thin-layer chromatography of the reaction mixture with the starting material indicated that no reaction had taken place, the reaction temperature was increased to 80°, where it was maintained for two hours, but again no reaction occurred. A small amount of triethylamine and 1 g of hydrogen sulfide were added to the solution. Heating was then continued at 85°. After 30 minutes reaction (as determined by thin-layer chromatography) was 40% complete. Small increments of triethylamine and hydrogen sulfide were added as heating continued until, after 21/2 hours at 85°, reaction was 95% complete. The solution was poured onto 150 ml of ice-water, and was purged with nitrogen gas to remove excess hydrogen sulfide. After 30 minutes, a solid formed, and was collected by filtration. The solid filter cake was washed with cold water and air-dried overnight to give 4.6 g of white solid 3-amino-2-cyano-3-(dimethylamino)propenethioamide, m.p. 186°-187° . The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) to provide the title compound as colorless powder (2.79 g, 68%). 1 H-NMR (CDCl3) 6: 3.41(3H,s), 3.63(3H,s), 5.59(2H,s), 7.38-7.50(4H,m), 7.65(1H,s), 7.68-7.81(4H,m).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a yellow powder (yield 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@@H:23]3[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]4([CH2:28][CH2:27]4)[CH2:25][NH:24]3)=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[CH3:40][N:24]1[C@H:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)=[O:22])[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl (6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (140 mg, 0.27 mmol) in methanol (3.0 mL) was added formaldehyde (37% solution in water, 0.5 mL) and sodium triacetoxyborohydride (0.25 g, 1.2 mmol). The mixture was then stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine. Dried and concentrated. tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) was obtained by column using CH2Cl2/Methanol (10%). ESI (M+H)+ 516.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1c(O)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-6-hydroxybenzoic acid (5.00 g, 32.029 mmol) in dimethyl formamide (200 mL) were added N,O-dimethylhydroxylamine hydro-chloride (6.25 g, 64.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.82 g, 48.043 mmol), 1-hydroxybenzotriazole (5.19 g, 38.435 mmol), and triethylamine (8.93 mL, 64.057 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide as an orange solid (4.320 g, yield; 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClC(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)([O-:10])=[O:9]
Reactant: NCc1ccc(CO)o1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1NCc1ccc(CO)o1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 15.9 parts of 4-chloro-3-nitropyridine, 12.7 parts of 5-(aminomethyl)-2-furanmethanol, 13.3 parts of N,N-diethylethanamine and 745 parts of trichloromethane was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was washed with K2CO3 (aq.), dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 17.76 parts (71.3%) of 5-[[(3-nitro-4-pyridinyl)amino]methyl]-2-furanmethanol; mp. 134.9° C. (interm. 19).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:9][CH2:8]1)=[N+:21]=[N-:22]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](COS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of crude butyl cis-4-{[(methylsulfonyl)oxy]methyl}-cyclohexane carboxylate (35.3 g, 117 mmol) in dimethylformamide (146 ml) was added sodium azide (30.4 g, 468 mmol, 4 equiv.). The mixture was stirred under nitrogen at 80° C. for eight hours. Approximately one-half of the dimethylformamide was distilled off (80° C. oil bath, 3.5 mm). The residue was diluted with water (750 ml) and extracted with ether (3×250 ml). The combined extract was washed with water (2×100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give crude butyl cis-4-(azidomethyl)cyclohexanecarboxylate (26.80 g, 98%) as a yellow oil.
Reaction SMILES: ClCC(O)=[O:4].[CH:6]([C:9]1[N:14]=[C:13](S)[N:12]=[C:11]([OH:16])[CH:10]=1)([CH3:8])[CH3:7].Cl>O>[CH:6]([C:9]1[N:14]=[C:13]([OH:4])[N:12]=[C:11]([OH:16])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: O=C(O)CCl
Reactant: CC(C)c1cc(O)nc(S)n1
Agent: Cl
Solvent: O
Product: CC(C)c1cc(O)nc(O)n1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Chloroacetic acid (22 g, 0.23 mol) and 6-isopropyl-2-mercaptopyrimidin-4-ol (10 g, 59 mmol) were suspended in water (150 mL). The reaction mixture was refluxed for 6 hours. Concentrated HCl (0.36 mL) was added carefully, and the reaction was returned to reflux for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 6-isopropylpyrimidine-2,4-diol (9.0 g, yield: 100%), which was used in the next step without further purification. LCMS (ESI) m/z: 155.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: ClC1C=CC(C[O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.[F:36][C:37]([F:41])([F:40])[CH2:38]I>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:38][C:37]([F:41])([F:40])[F:36])=[CH:13][N:12]=1
Reactant: FC(F)(F)CI
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCC(F)(F)F)cn1

Procedure:
Compound 12 was prepared in a similar manner to compound 1 from 1,1,1-trifluoro-2-iodoethane to afford a pale yellow solid (23.0 mg, 50%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.27 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.21 (br s, 1H), 6.78-6.73 (m, 1H), 6.69-6.66 (m, 1H), 5.55 (d, J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 4.43 (q, J=8.0 Hz, 2H). MS (ESI): m/z 452.1 [M++1]. HPLC: 98.05%.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:16]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:15]=[CH2:14]
Reactant: C=CC[Si](C)(C)C
Reactant: OC1(c2ccccc2)CCCCO1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1(c2ccccc2)CCCCO1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-phenyltetrahydro-2H-pyran-2-ol (1.066 g, 5.98 mmol) and allyltrimethylsilane (1.901 mL, 11.96 mmol) in CH2Cl2 (25 mL) at 0° C. was added BF3.OEt2 (0.758 mL, 5.98 mmol) dropwise, and the mixture was stirred at the same temperature for 1 hr. Then the reaction was quenched with saturated NaHCO3 and the product was extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with 1:9 followed by 4:6 EtOAc-hexane to give 2-allyl-2-phenyltetrahydro-2H-pyran as oil (0.954 g). 1H NMR (400 MHz, CCl3D) δ ppm 7.10-7.45 (5H, m), 5.47-5.65 (1H, m, J=17.19, 10.11, 7.33, 7.33 Hz), 4.84-5.00 (2H, m), 3.64-3.78 (1H, m), 3.41-3.57 (1H, m), 2.35-2.48 (1H, m), 2.20-2.35 (1H, m), 1.55-1.81 (4H, m), 1.35-1.54 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CS(C)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 3.7 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.71 g, 3.7 mmol). The product was isolated as a white foam. Yield 1.17 g (69%). mp 140°-145° C. FDMS m/e=455 (M+ of free base). α[D]589 =+4.59 (c=1.00, dimethylsulfoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 0.5 mmol), 4-bromomethyl-pyridine (98 mg, 0.6 mmol) and Cs2CO3 (245 mg, 0.75 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as little yellow solid (140 mg, 76%). LC/MS m/e calcd. for C22H17ClN2O: 360, observed (M+H)+: 361.2 1HNMR (400 MHz, MeOD-d4) δppm 2.22-2.37 (m, 2 H) 3.32-3.40 (m, 1 H) 5.39 (s, 2 H) 6.15 (d, J=7.58 Hz, 1 H) 6.74-6.85 (m, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.10-7.19 (m, 1 H) 7.24-7.42 (m, 4 H) 7.93 (d, J=6.32 Hz, 2 H) 8.80 (d, J=6.06 Hz, 2 H). MS calcd. for C22H17ClN2O 360, obsd. (ESI+) [(M+H)+] 361.1.
Reaction SMILES: O.[C:2]12([CH3:12])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:11].C[C@H]1C[C@@H:18]([OH:20])[C@H:17](C(C)C)CC1>C(O)C>[C:2]12([CH3:12])[C:8]([CH3:9])([CH3:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH2:17][CH2:18][OH:20])[OH:11]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: CCO
Solvent: O
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
5 l of distilled water is added to 233.3 g of the genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 137 g of Borneol, and 0.5 l of l-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: [Na].[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)([O:4]CC)=O.Cl.[C:15]([NH2:18])(=[NH:17])[CH3:16]>C(O)C>[CH3:16][C:15]1[NH:18][C:2](=[O:4])[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc2c(c(=O)[nH]1)CCCC2
Temperature: 25 °C

Procedure:
To 50 mL of absolute ethanol under a nitrogen atmosphere was added 5.65 g of sodium metal. After all the sodium had reacted, 20.15 g of 2-carboethoxycyclohexanone was added followed by 14.50 g of acetamidine hydrochloride. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. Successive crops of solid were collected by concentration of the mother liquors (13.1 g, 65%): 1H NMR (DMSO-d6, 300 MHz) δ 12.18 (s, 1H), 2.22 (m, 2H), 2.15 (m, 2H), 2.10 (s, 3H), 1.65 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[ClH:22]>>[ClH:22].[N:1]1[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)c1cnc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COC(=O)c1cnc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
A round-bottom flask containing 7-tert-butyl 3-methyl 5,6-dihydro-1,7-naphthyridine-3,7-(8H)-dicarboxylate (0.470 g, 1.61 mmol) and hydrochloric acid (6.03 mL, 24.1 mmol, 4.0 M in 1,4-dioxane) was stirred at rt for 1 h. The solution was then completely evaporated to yield methyl 5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (0.440 g, 100%). LC-MS: (FA) ES+ 193; 1H NMR (Methanol-d4, 400 MHz) δ9.26 (s, 1 H), 8.87 (s, 1 H), 4.83 (s, 2 H), 4.03 (s, 3 H), 3.69 (m, 2 H), 3.43 (t, J=5.5 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:18][CH2:17]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)CN(CCCCN)CC2
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 5-methylsalicylic acid (0.691 g, 4.5 mmol), 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butan-1-amine (1.0 g, 3.8 mmol), N,N′-Dicyclohexylcarbodiimide (DCC) (0.94 g, 4.5 mmol) and 1-Hydroxybenzotriazole hydrate (HOBOt) (0.61 g, 4.5 mmol) in dichloromethane (20 mL) was stirred overnight under an atmosphere of nitrogen. The reaction mixture was washed with saturated sodium bicarbonate solution (3×10 mL). The organic solution was dried over Na2SO4 and volatiles were removed under reduced pressure. The residue was purified by silica gel column with methanol/ether (5/95, v/v) as the mobile phase to afford 4a as a viscous oil (1.39 g; 93%). 1H NMR (300 MHz, CDCl3): 1.70-1.78 (m, 4H), 2.09 (s, 3H), 2.50-2.60 (m, 2H), 2.68-2.76 (m, 2H), 2.78-2.88 (m, 2H), 3.44-3.60 (m, 4H), 3.82 (s, 3H), 3.83 (s, 3H), 6.48 (s, 1H), 6.58 (s, 1H), 6.83-6.87 (d, 1H), 7.00-7.04 (m, 1H), 7.10-7.16 (m, 1H), 7.70-7.90 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:25][CH:24]=2)[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 2,6-dichloronicotinamide (100 mg, 0.524 mmol) and 4-(4-methylpiperazin-1-yl)aniline (300 mg, 1.571 mmol) in THF (5 mL) was cooled to −78° C. and treated with 1 M solution of lithium bis(trimethylsilyl)amide (3.14 mL, 3.14 mmol) in THF. The reaction mixture was stirred at −78° C. for 1 h and then at rt for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated. The residue was purified by MPLC chromatography (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 131 mg of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=346.09, 348.05 (Cl pattern). 1H NMR (400 MHz, CDCl3-MIX) δ ppm 10.56 (1H, s), 7.59 (1H, d, J=7.91 Hz), 7.56 (2H, d, J=8.79 Hz), 6.93 (2H, d, J=9.23 Hz), 6.61 (1H, d, J=7.91 Hz), 5.76 (2H, br. s.), 3.16-3.21 (4H, m), 2.57-2.62 (4H, m), 2.36 (3 H, s).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36][CH2:37]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccccc2)nc1CCCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 79 %

Procedure:
Intermediate 60 was prepared as described above for the preparation of intermediate 52. From 266 mg of N-(Boc)-L-Tyrosine methyl ester and 208 mg of Intermediate 8F was prepared 360 mg of BOC-protected intermediate methyl ester (79% yield; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.46-7.44 (m, 3H), 7.04 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.97 (d, 1H, J=7.6), 4.57 (m, 1H), 3.99 (t, 2H, J=6.0), 3.74 (s, 3H), 3.05 (m, 2H), 2.77-2.65 (m, 4H), 2.19 (t, 2H, J=6.6), 1.45 (s, 9H), 1.24 (t, 3H, J=7.5); From 352 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 60. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield intermediate 60; 1H NMR (DMSO-d6, 400 MHz) δ7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J=8.5), 6.82 (d, 2H, J=8.5), 3.92 (t, 2H, J=6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J=14.3, 4.8), 2.8 (dd, 1H, J=14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13 (t, 3H, J=7.4); low resolution MS (ES+)m/e 392.9 (MH+); TLC Rf=0.44 (4/1, DCM/MeOH).