Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([NH2:30])([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:28]([NH:30][CH2:35][CH:32]3[CH2:34][CH2:33]3)([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:22])([F:21])[F:23])[N:9]=2)[N:7]=1
Reactant: CC1(N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(NCC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step B (20 mg, 0.045 mmol) in MeOH (45.2 μl) and DCM (45.2 μl) was added cyclopropanecarbaldehyde (3.17 mg, 0.045 mmol) followed by sodium triacetoxyborohydride (28.7 mg, 0.136 mmol). The reaction was stirred for 3 h at room temperature and was quenched with aqueous NaHCO3. The solution was extracted with EtOAc. The organic layer was dried (sodium sulfate), concentrated in vacuo and purified by silica gel column chromatography to afford the title product as a white solid. 1H NMR (500 MHz, CHCl3-d): δ 9.20 (s, 1H); 8.77 (d, J=8.07 Hz, 1H); 8.56 (dd, J=4.53, 1.58 Hz, 1H); 7.13 (dd, J=8.08, 4.50 Hz, 1H); 5.55 (s, 2H); 4.95-4.88 (m, 3H); 2.88-2.74 (m, 2H); 2.27 (dd, J=11.46, 6.00 Hz, 1H); 2.20-1.94 (m, 1H); 1.54 (s, 3H); 0.87-0.80 (m, 1H); 0.48-0.37 (m, 2H); 0.05-0.00 (m, 2H). m/z=497.1 (M+H).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]COC(C)=O.O>CN(C=O)C>[C:14]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[CH2:12][CH:11]([O:13][CH3:22])[CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(diphenylmethyl)-3-azetidinol hydrochloride (5.0 g) in DMF (25 ml), was added sodium hydride under ice-bath cooling. After 10 minute stirring at the same temperature, the mixture was allowed to warm to 25° C. and then stirred for 15 hours. EtOAc (500 ml) and water (200 ml) were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; 200 ml, toluene:EtOAc=15:1-8:1) to give 1-(diphenylmethyl)-3-methoxyazetidine (3.41 g).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[O:25])[C:6]1=[O:29]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)-N-methylmethanesulfonamide employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a cream-colored solid: 1H NMR (d6-DMSO) δ 10.20 (1H, br t, J=6 Hz), 8.51 (1H, s), 7.76 (1H, s), 7.31 (2H, dd, J=8.3, 6 Hz), 7.12 (2H, t, J=˜9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.55 (2H, q, J=6 Hz), 3.25 (2H, m), 3.12 (3H, s), 2.85 (3H, s), 2.81 (3H, s), 2.79 (3H, s); HRMS calcd for C24H28FN5O6+H+: 534.1823. Found: 534.1812.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:42])[C@H:18]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])[CH3:19]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C@H:18]([CH3:19])[C:17]([O:16][CH3:15])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:44]2[CH2:45][CH2:46][CH2:47][CH:42]([OH:41])[CH2:43]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(CN4CCCC(O)C4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 34.3 %

Procedure:
In a similar manner to Step 2 of Example 147, 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (104 mg, 0.188 mmol) was dissolved in acetonitrile (5.2 mL), and the solution was treated with 3-hydroxypiperidine (76.0 mg, 0.752 mmol), acetic acid (0.215 mL, 3.76 mmol) and sodium triacetoxyborohydride (160 mg, 0.752 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(3-hydroxypiperidinomethyl)indol-2-yl]isoindolinone (40.9 mg, yield 34%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1.CS(C)=O>CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzaldehyde 57 (5.099 g, 27 mmol), cesium carbonate (9.48 g, 29 mmol), and methyl piperidine-4-carboxylate (4 mL, 27 mmol) was added DMSO (27 mL). The reaction mixture was heated to 100° C. for 30 min and diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-nitrophenyl)piperidine-4-carboxylate 58 (3.45 g, 43% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1. found 293.1 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid methyl ester (1.02 g, 2.70 mmol) in a 1:1 solution of tetrahydrofuran:water (30 mL) was treated with lithium hydroxide monohydrate (270 mg, 5.40 mmol). The mixture was stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran, diluted with water and the pH adjusted to pH=5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid (766 mg, 78%) as a cream colored solid: HR-ES-MS m/z calculated for C15H13NO4ClF3 [M+H]+ 364.0558, observed 364.0557.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C[CH2:15][N:16]=[C:17]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CNC>C1COCC1>[CH3:15][N:16]([CH3:17])[C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-1H-indole-2-carboxylic acid (2.40 g, 10.0 mmol) in THF (100 mL) were added EDCl (2.11 g, 30.0 mmol), HOBt (1.49 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, a solution of N,N-dimethyl amine (2.0 M solution in THF, 15 mL, 30.0 mmol) was added. The mixture was stirred for 16 hours at room temperature. Solvent was evaporated, the residue was taken in ethyl acetate (200 mL), and water (200 mL) was added. The organic phase was separated; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated and dried under vacuum to give 5-bromo-1H-indole-2-carboxylic acid dimethylamide as an off-white solid. Yield: 2.56 g (96%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C)ccc43)cc2s1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred solution of 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.61 g, 1.8 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.40 g, 1.57 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.57 g, 89%) as a yellow solid which was not purified further.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=O)=[O:5].Cl.[CH3:11][NH2:12].C(O)(=O)C.C[O-].[Na+]>O>[Cl:1][C:2]1[C:7](=[O:6])[N:12]([CH3:11])[C:4](=[O:5])[C:3]=1[Cl:9]
Reactant: CN
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A 3L-three-necked flask fitted with a magnetic stir bar, digital thermocouple/thermometer, nitrogen purge and solid addition funnel was charged with 450 g (269.5 mol) of dichloromaleic anhydride, 191 g (282.8 mol) of methylamine hydrochloride and 1.6 L of acetic acid. The reaction mixture was then cooled to 10° C., and 160 g NaOMe added from the solid addition funnel over 1 hour while keeping the temperature between 10°-12° C. The reaction mixture was allowed to stir at room temperature for 42 hours (24 hours is sufficient) then heated to 100° C. for 3 hours. HPLC analysis at this time indicated that all the starting material had disappeared. The reaction was cooled to room temperature and 2L water was added. The mixture was then cooled to 3°-10° C. for 1 hour and filtered at 4° C. The solids were then rinsed with 2L of cold deionized water. The pale yellow solid dried in an air oven overnight to afford 360 g (75%) yield of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23][SH:24])[CH3:20].O>CN(C=O)C>[CH2:19]([O:21][C:22]([C:23]1[S:24][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=1)=[O:25])[CH3:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-5-nitro-benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 0° C. was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7 mmol). After stirring at 0° C. for 20 min, the resulting mixture was allowed to warm to rt and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([OH:20])[CH2:18][CH3:19]>>[CH2:17]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: CCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCOCCCCCCCCCC(=O)O
Temperature: 102 °C
Reaction time: 18 h

Procedure:
10-bromodecanoic acid (1g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893g, 15.9 mmol) in n-propanol (30 mL) and stirred at 102° C. for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a yellow oil. The product was purified by silica column chromatography in 2% diethyl ether/methylene chloride/0.2% formic acid, and then in 7% ethyl acetate/hexane/0.3% formic acid. Recrystallization from hexane at -20° C. yielded 10-(propoxy)decanoic acid (74 mg, 12%: mp <30° C.; 1H NMR (300 MHz, CDC13) δ 0.91 (t, 3H, J=7.5, CH3), 1.18-1.40 (br, 10H, methylene envelope), 1.48-1.67 (bm, 6 H, CH3CH2CH2OCH2CH2, CH2CH2COOH), 2.33 (t, 2H, J=7.4, CH2COOH), 3.31-3.45 (bm, 4H, CH2OCH2), 10.37 (br, 1H COOH); 13C NMR (75.4 MHz, CDC13) 10.67, 22.94, 24.72, 26.19, 29.09, 29.22, 29.41, 29.74, 34.11, 70.88, 72.53, 179.69; m/z 231 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:16].[Na+]>CC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: ClCCCCCCCCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCCCc1ccccc1

Procedure:
A mixture of 8-phenyloctyl chloride (4.4 g), sodium iodide (5.34 g) and acetone (20 ml) was heated under reflux for 20 hours. Evaporated, water (20 ml) added and extracted with diethyl ether (20 ml). The extracts were dried, filtered and evaporated to a pale yellow liquid (5.5 g). Distilled to give 8-phenyloctyl iodide, b.p. 200° C. (air bath temperature) at 0.1 mBar.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC[O-].[Na+].[CH2:10]([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:11]=[CH2:12]>CCO>[CH2:10]([C:13]1[C:19]([OH:20])=[N:4][C:3]([NH2:5])=[N:2][C:14]=1[OH:15])[CH:11]=[CH2:12]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCc1c(O)nc(N)nc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Guanidine hydrochloride (27 g, 0.28 mol) was added to cold absolute EtOH (200 mL) and NaOEt (30% in ethanol) (200 mL), and the mixture was stirred at 0° C. for 10 min. After this time, diethyl allylmalonate (55 g, 0.28 mol) was added. The reaction mixture was then stirred at room temperature for 18 h. Acidification with 3N HCl precipitated the crude product (pH=6). The solid was collected by filtration and washed with ethanol. Recrystallization from water afforded 29 g (62%) of pure 5-allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII). LCMS (ESI) m/z=168 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([C:15]([CH3:22])([CH3:21])[O:16]4)[C:11]=3[N+:12]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>[Pd].C(O)C>[C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([C:15]([CH3:22])([CH3:21])[O:16]4)[C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC12CCC(c3c1nnc(-c1ccccc1)[n+]3[O-])C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC12CCC(c3nc(-c4ccccc4)nnc31)C(C)(C)O2

Procedure:
To a solution of 1.80 g. (0.006 mole) 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide and 1.50 g. (0.018 mole) cyclohexene in 30 ml. absolute ethanol there is added 60 mg. 10% palladium on charcoal. The resulting mixture is refluxed under a nitrogen atmosphere for 18 hours. The catalyst is then removed by filtration and the filtrate evaporated to give 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine; m.p. 180° to 189° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCCSc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCSc2ccccc2)CC1
Yield: 42.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.5 g) as starting compound and 6-phenylthiohexyl chloride (2.76 g) were reacted and treated in the same manner as in Example 168 to give 1.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-phenylthiohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].Cl.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)C.C(OCC)C>[O:12]1[CH2:11][CH2:10][N:9]([C:6]2[N:5]=[N:4][C:3]([NH:1][N:2]3[CH:18]=[CH:22][CH:21]=[CH:20]3)=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: COC1CCC(OC)O1
Reactant: NNc1ccc(N2CCOCC2)nn1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: c1ccn(Nc2ccc(N3CCOCC3)nn2)c1
Temperature: 60 °C
Yield: 2 %

Procedure:
To 5.85 g (30 m mol) of 3-hydrazino-6-morpholino-pyridazine in 130 ml of ethanol, ethyl ether (45 ml) saturated with hydrogen chloride is added. The suspension of pale yellow precipitate which forms is additioned with 12 g (90 m mol) of 2,5-dimethoxytetrahydrofuran and the mixture is refluxed (60° C.) for 6 hours. The solvent is removed under vacuum and the residue is dissolved in water, brought to pH 8 by addition of a sodium carbonate solution and extracted with four portions (each of 100 ml) of dichloromethane. The organic extracts are pooled together, washed with water (50 ml) and anhydrified over sodium sulfate. Evaporation of the solvent yields an oil which is purified through column chromatography (silicagel, 500 g) using as the eluent a mixture of dichloromethane and ethyl acetate wherein the ratio of ethyl acetate is gradually increased from 20% to 100%. Evaporation of the more polar fraction yields 0.15 g (2%) of the product of the title which melts at 228° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (+/−)-ethyl 4-(1-{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}butyl)benzoate (26 mg, 0.064 mmol) was dissolved in methanol (0.13 ml) and tetrahydrofuran (0.070 ml) and treated with aqueous 2.0M lithium hydroxide (64 ul, 0.13 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo and the residue was acidified with aqueous 1.0M hydrochloric acid. The crude product was concentrated in vacuo a second time and was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a solution of N2-butyl-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (310 mg) in dry methanol (30 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (5.5 ml) in one go. The reaction was left to stir at room temperature for 16 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (10 ml) and the solid filtered and dried on the rotary evaporator (60° C.) for 30 minutes. This afforded the title compound as a solid (170 mg).