Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1.CO>[NH:14]1[CH2:15][CH2:16][CH:11]([O:10][CH2:9][CH2:8][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C1CCN(CCOC2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 N HCl solution in dioxane (6 mL) was added to a solution of tert-butyl 4-(2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (114)(6.5 g, 20.80 mmol) in MeOH (16 mL) and the reaction mixture was stirred at room temperature for 6 hours. Removal of solvent afforded 1-(2-(piperidin-4-yloxy)ethyl)piperidine as its hydrochloride salt (0.540 g, 12.22%). This salt was then dissolved in methanol (50 ml) and MP-carbonate (14.88 g, 33.61 mmol) was added. The resulting mixture was filtered and the solvent removed to give the desired material a colourless liquid which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 1.33-1.47 (2H, m), 1.50-1.71 (3H, m), 1.86-1.96 (4H, m), 2.50-2.67 (6H, m), 3.00-3.14 (4H, m), 3.34 (1H, septet), 3.55 (2H, t), 3.60 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Temperature: 0 °C

Procedure:
Fuming H2SO4 (25 mL) is added dropwise to a solution of crude 3-chloro-pyridine-1-oxide in concentrated H2SO4 (25 mL) with cooling (0° C.) and stirring. HNO3 (fuming, 90%, 60 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and then allowed to warm up to room temperature slowly. The resulting mixture is then heated at 120° C. for 4 hours with stirring, cooled, and poured into ice-cold water, and extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 3-chloro-4-nitro-pyridine-1-oxide as an yellow solid (10 g) ; 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J=1.5 Hz, 1H), 8.13 (dd, J=1.5, 5.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]CN(C(C)C)C(C)C.CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:16])[CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1NCC2CC21c1ccc(Cl)c(Cl)c1
Solvent: CI
Solvent: CN(C)C=O
Product: CC1N(C)CC2CC21c1ccc(Cl)c(Cl)c1

Procedure:
To a dried, 5 mL round-bottomed flask was added (±)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane, Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide was added drop wise with stirring over 5 min and the resulting solution stirred under ambient temperature overnight. The solution was concentrated under reduced pressure and purified after drying. The residue was purified by HPLC which failed to remove the impurities. This was further purified on a prep TLC plate eluting with 20/1 CHCl3/MeOH (v/v). The desired band was collected, extracted with CHCl3/MeOH, and concentrated after filtration to afford the desired free base. Yield: 0.005 g 15%; LCMS (+)ESI: m/z=256 [MH]+ (100); 258 [MH+2]+; (65); 1H NMR (300 MHz, CDCl3) δ□: 7.33 (d, H, J=12 Hz, ArH), 7.32 (d, 1H, J=2 Hz, ArH), 7.08 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.31 (q, 1H, J=6 Hz, CHNH2), 2.83 (s, 2H, CH2N), 2.32 (s, 3H, NCH3), 1.79 (m, 1H, CH2CH), 1.40 (t(br), 1H, ArCCH2), 0.73 (d, 3H, J=7 Hz, CHCH3)., 0.60 (dd, 21-1, J=8 Hz, 4 Hz, ArCCH2); 13C NMR (75 MHz, CDCl3) δ□: 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9, 18.4, 11.6.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:18](=[O:19])[N:17]=[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[NH:15][C:14]3=[O:33])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:38](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:14]([O:33][CH3:38])=[N:15][C:16]([N:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:24][CH2:25]4)=[N:17][C:18]3=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nc(N2CCN(c3ccc(F)cc3)CC2)nc(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 7 %

Procedure:
To an N,N-dimethylformamide solution (4 mL) of a crude product (0.69 mmol) of 3-{4-[(4-chlorobenzyl)oxy]benzyl}-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione, potassium carbonate (332 mg, 2.40 mmol) and methyl iodide (137 μL, 2.20 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the title compound (26 mg, two step yield: 7%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: Brc1ccc2nc(CC3CCNCC3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-ylmethyl)benzo[d]thiazole (380 mg, 1.221 mmol) and 2-chloro-5-propylpyrimidine (249 mg, 1.587 mmol) in DMF (8 mL) was added potassium carbonate (675 mg, 4.88 mmol). The reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 6-bromo-2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazole (252 mg, 0.584 mmol, 48% yield) as a light brown solid. LCMS (m/z)=432 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 2-Morpholin-4-yl-ethanol. LC/ESI-MS: m/z=324 [M+H].
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][N:26]([CH3:43])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[OH:34])=[CH:29][CH:28]=1.CN(C)C1C=CC(C(C#C)O)=CC=1>C(OCC)C>[CH3:43][N:26]([CH3:25])[C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:34])[C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(C(O)C#Cc2ccncc2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: C#CC(O)c1ccc(N(C)C)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)C#Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (1.75 g) and methylene chloride (20 mL) under argon atmosphere and cool to 0° C. Add a 1:1 mixture of 4-dimethylamino-α-[(4-pyridinyl)ethynyl]-benzenemethanol and 4-dimethylamino-α-(ethynyl)-benzenemethanol (0.8 g). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography (2:1 ethyl acetate/hexane) to yield 0.94 g of the title compound; mp 143°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=C)=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[O-:38]I(=O)(=O)=O.[Na+].O>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[O:38])=[CH:28][CH:27]=2)(=[O:24])=[O:25])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(C=O)cc2)ncnc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
318 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide, 5.3 mg of osmium tetroxide and 270 mg of sodium(meta)periodate were added in succession to a mixture of 1.5 ml of water and 4 ml of dioxane at room temperature. After stirring at room temperature for 1 hour, the dioxane was distilled under reduced pressure. Thereafter, the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate was washed twice with water and once with NaCl solution (saturated), dried and distilled under reduced pressure. The residue was chromatographed over 30 g of SiO2 with CH2Cl2 /ethyl acetate and yielded 150 mg of rac-p-[[5-(o-methoxybenzyl)-6-[2-[(tetra-hydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]sulfamoyl]-benzaldehyde as white foam. MS: 527 (M); 443 ##STR12## (--OCH3 +SO2).
Reaction SMILES: N[C:2]1C=CC2N=CSC=2C=1.[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH3:2][NH:36][S:33]([C:27]1[CH:26]=[CH:25][C:30]([NH:31][N:32]=[C:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]4[C:22]=3[S:11][CH:12]=[N:13]4)[NH:18][C:19]2=[O:24])=[CH:29][CH:28]=1)(=[O:34])=[O:35]
Reactant: Nc1ccc2ncsc2c1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C1Nc2ccc3ncsc3c2C1=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
6H-1-Thia-3,6-diaza-as-indacene-7,8-dione was prepared from 6-aminobenzothiazole according to Procedure A: 1H NMR (DMSO-d6): δ 7.10 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 9.35 (s, 1H), 1.19 (s, 1H); ESI−MS m/z 204 (M)−. The title compound was prepared from 6H-1-thia-3,6-diaza-as-indacene-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>260° C.; 1H NMR (DMSO-d6): δ 2.39 (d, J=5.1 Hz, 3H), 7.12 (d, J=8.4 Hz, 1H), 7.32 (q, J=5.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.6 Hz, 1H), 9.30 (s, 1H), 11.26 (s, 1H), 12.69 (s, 1H); APCI−MS m/z 387 (M)−. Anal. Calcd for C16H13N5O3S2.0.33 H2O: C, 48.85; H, 3.50; N, 17.80; S, 16.30. Found: C, 48.89; H, 3.40; N, 17.67; S, 16.23.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Yield: 7.7 %

Procedure:
A solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (150. mg, 0.32 mmol), piperidine (0.03 mL, 0.32 mmol) and 2-methyl-2-(1-piperidyl)propanal (74.08 mg, 0.48 mmol) in ethanol (8 mL) was heated in a sealed tube at 90° C. for 16 hrs. The solution was cooled and concentrated. The residue was dissolved in ethyl acetate and washed with 5% citric acid and brine and then dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 grams column at 0% to 6% MeOH/ethyl acetate) to obtain 15 mg (8%) of the title compound. MS (pos. ion) m/z: 609 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=[O:23]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:21][C:22](=[O:23])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: CSc1ccc(NC(=O)CBr)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)Nc2ccc(SC)cc2)c1=O
Yield: 90 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2-bromo-4′-(methylthio)acetanilide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 90.0%.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=O)[CH:9]=[C:10]([CH:13]=1)[CH:11]=O)[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:9]=[C:10]([CH2:11][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]=1)[CH3:2]
Reactant: CC(C)CNCCCNCCCN
Reactant: CCC(CC)COc1cc(C=O)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)COc1cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c1
Reaction time: 24 h

Procedure:
5-(2-Ethylbutoxyl)isophthalaldehyde (0.20 g, 0.88 mmol) and MeOH (15 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (0.33 g, 1.76 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.13 g, 3.52 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[C:26]([NH:34][C:35](=[S:36])[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(=O)c3ccccc3)nc21
Temperature: 0 °C
Yield: 88.4 %

Procedure:
A solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 234 mg, 0.69 mmol) and benzoyl isothiocyanate (0.1 ml, 0.83 mmol) in acetone (3 ml) was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and water was added. The resulting brown solid was collected by filtration and air-dried to give 4-(3-benzoylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (306 mg, 88% yield)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C1(=O)O[CH2:15][CH2:14][O:13]1.N1C=CN=C1.C(=O)=O>C(OCC)C>[OH:13][CH2:14][CH2:15][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: O=C1OCCO1
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1OCCO
Reaction time: 18 h

Procedure:
A mixture of 74.6 g of (0.43 mol) of 2-hydroxybenzenesulfonamide, 45.3 g (0.51 mol) of ethylene carbonate and 0.9 g of imidazole was heated to 160° with vigorous stirring. After about four hours the carbon dioxide solution had subsided and no unreacted 2-hydroxybenzenesulfonamide was present in the reaction mixture. The mixture was allowed to cool and about 400 ml of diethyl ether was added to the thick oil. The two-phase mixture was stirred vigorously and was heated to reflux for about one hour. The diethyl ether was decanted off and a fresh portion of diethyl ether was added. The mixture was again stirred and heated to reflux. After the diethyl ether was decanted off a fresh portion of diethyl ether was added and the mixture was allowed to stand at ambient temperature for about 18 hours. The resulting light brown solid was isolated by filtration and was recrystallized from nitromethane to afford 49 g (53%) of trum exhibited a broad peak at approximately 3400 cm-1 consistent with the primary alcohol of the product and peaks at 3370 cm-1 and 3270 cm-1 consistent with the NH2 of a primary sulfonamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH:6][CH3:7].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.O>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH3:7]
Reactant: CNCCCNC
Reactant: Brc1nccs1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNCCCN(C)c1nccs1
Temperature: 120 °C
Yield: 60 %

Procedure:
2.45 g (24.0 mmol) N,N3-dimethylpropane-1,3-diamine was added to 0.36 ml (4.0 mmol) 2-bromothiazole and heated to 120° C. for 1 h. After cooling to RT, dilution with water and chloroform took place. The phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, DCE/MeOH/25% aq. NH3-soln 4:4:1) was carried out on the residue, yielding 440 mg (2.4 mmol, 59%) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: Clc1nccnc1OC1CCCN(c2ccc3ccccc3n2)C1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: OCC1CCN(c2nccnc2OC2CCCN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (racemix mixture) (see PREPARATION P2.3; 0.1 g, 0.29 mmol) and piperidin-4-ylmethanol (0.033 g, 0.29 mmol) and K2CO3 (0.08, 0.58 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.020 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 420 calc. for C24H29N5O2 419.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[S:17]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH3:31])([CH3:30])[CH2:22][CH2:21]1)(=[O:19])=[O:18])C(OC)=O.[Na+].[Cl-]>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[S:17]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH3:30])([CH3:31])[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 79.7 %

Procedure:
2-[4-Bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-malonic acid dimethyl ester (0.72 g, 1.32 mmol) was heated at 120° C. for 5 hrs in DMSO which contained NaCl (153.5 mg, 2.65 mmol) and 2 drops of water. After cooling to rt, the mixture was extracted with ethyl acetate, washed with water and brine, and was dried over MgSO4. Filtration and concentration yielded a residue which was purified via silica gel flash column chromatography eluting with hexane/ethyl acetate (100/15) to give 2-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-acetic acid methyl ester (512 mg). MS: 487.9 (M+H)+; tR=2.75 min (method 1)
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:41])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+:44]>C1COCC1.O>[Na+:44].[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:26]1[O:27][C:28]([C:29]([F:32])([F:30])[F:31])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([O-:42])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:41])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2,6-dichlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetate methyl ester (150 mg, 0.239 mmol) was put into THF/water (20 mL, 3:1) solvent, then NaOH (14.37 mg, 1.437 mmol) was added thereto and stirred at room temperature for 24 hours. After THF was removed, a desired sodium salt solid was washed with water to obtain a final compound (150 mg, 98%).