Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:7]1)=[O:5])[CH3:2].[CH:17]1[C:30]2[C:21](=[CH:22][C:23]3[C:28]([C:29]=2[C:31](Cl)=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:16][CH2:15][N:14]([C:31]([C:29]3[C:30]4[C:21]([CH:22]=[C:23]5[C:28]=3[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:32])[CH2:13]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCNC2)C1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)C2)C1
Yield: 100 %

Procedure:
The mixture of ethyl and isopropyl esters (1.23 g) was dissolved in anhydrous ethanol (˜50 mL) and dilute hydrochloric acid (2N, 4 mL) and 10% palladium on carbon (120 mg) was added. The suspension was shaken under hydrogen (48 psi) in a Parr shaker for 16 hr. Only a very small amount reduction occurred so the catalyst was filtered off and the solvent removed under vacuum. The residue was dissolved in glacial acetic acid, platinum (IV) oxide (100 mg) was added and the suspension shaken under 50 psi hydrogen at 60° C. overnight. The solvent was evaporated under vacuum, the residue dissolved in dichloromethane/methanol and the catalyst was filtered off though Celite®. The solvent was again evaporated and the residue partitioned between dilute hydrochloric acid and ethyl acetate (×3). The aqueous layer was made basic with 14% w/v sodium hydroxide and re-extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The product was purified by chromatography on silica gel eluting with 5%-10%-40%-methanol-dichloromethane to give (3R)-1-pyrrolidin-3-yl-piperidine-3-carboxylic acid ethyl ester (36.9 mg). This amine was reacted with anthracene-9-carbonyl chloride (Intermediate 3) by a procedure analogous to that described above for the preparation of Example 1 to give the title compound (70.1mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21]>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(F)cc(Cl)c2)cc1
Solvent: CCCCCCC
Product: Fc1cc(Cl)cc(C#Cc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-chloro-5-fluoro-phenyl ester and ethynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 98%); 1H NMR δ (CDCl3): 7.51 (m, 2H), 7.36 (m, 3H), 7.03 (d, J=7.05 Hz, 2H), 6.79 (t, J=8.35 Hz, 1H); LCMS m/z: 230.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:35][CH:34]3[N:19]([C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]4[C:31]([C:37]([OH:39])=O)([NH:32][C:33]3=[O:36])[CH2:30]4)[CH2:18]2)[C:13]2[C:8](=[C:9]([CH3:43])[C:10]([O:41][CH3:42])=[CH:11][CH:12]=2)[N:7]=1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:85][S:86]([CH:89]6[CH2:91][CH2:90]6)(=[O:88])=[O:87])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:35][CH:34]3[N:19]([C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]4[C:31]([C:37]([NH:85][S:86]([CH:89]5[CH2:91][CH2:90]5)(=[O:88])=[O:87])=[O:39])([NH:32][C:33]3=[O:36])[CH2:30]4)[CH2:18]2)[C:13]2[C:8](=[C:9]([CH3:43])[C:10]([O:41][CH3:42])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(thiazol-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 25 following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=708 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[C:26]([Cu])#[N:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccc(OC)cc3)cccc2c1O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccc(OC)cc3)cccc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=351.4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([CH3:16])[C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18].[H-].[Na+].[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]I)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C:10](=[O:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:18])(=[O:23])[CH3:22]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccco1
Reactant: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Reaction time: 0.42 h
Yield: 77.9 %

Procedure:
To a stirring suspension 3-(2-furylmethyl)-7-methylxanthine (0.40 g, 1.62 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (41 mg, 1.71 mmol) in one portion. After stirring for 25 minutes, (R)-5-acetoxy-1-iodohexane (0.46 g, 1.71 mol) was added neat. After stirring at room temperature for 72 hours, the reaction was quenched by the addition of water (75 ml) and extracted with ethyl acetate (3×35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (2×35 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.49 g, 78% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:4]1[CH:3]=[C:2]([F:1])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:34]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 165 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (5.00 g, 17.2 mmol) in acetone (86.0 mL) was treated with aq 2 N K2CO3 (13.0 mL, 25.8 mmol) and ethyl bromoacetate (1.50 mL, 9.66 mmol) and heated to 50° C. for 2 h. The solution was cooled to 0° C. and acidified to pH of 1 with 2 N HCl. The solution was diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC(10–100% ethyl acetate in heptane, 23 mL/min, 75 min) to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester as a pale yellow solid (6 g, 93%): mp 78–80° C.; Rf 0.26 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 9.01 (t, J=6 Hz, 1 H), 8.19 (t, J=1.8 Hz, 1 H), 8.10 (dd, J1=8.1 Hz, J2=1.5 Hz, 1 H), 7.89 (dd, J1=8.7 Hz, J2=6.9 Hz, 1 H), 7.79 (d, J=7.5 Hz, 1 H), 7.61 (t, J=8.1 Hz, 1 H), 7.11 (dd, J, =11.1 Hz, J2=2.4 Hz, 1 H), 6.92 (dt, J1=8.4 Hz, J2=2.4 Hz, 1 H), 5.0 (9, 2 H), 4.63 (d, J=6.3 Hz, 2 H), 4.15 (q, J=7.2 Hz, 2 H) 1.17 (t, J=6.5 Hz, 3 H). ESI-LC/MS m/z calcd for C18H17FN2O6: 376.4. Found 377.0 (M+1)+. Anal. calcd for C18H17FN2O6: C, 57.45; H, 4.55; N, 7.44. Found: C, 57.47; H, 4.64; N, 7.28.
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:13](Br)[CH3:14].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C@H:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C[C@@H]1C=CCC(C)(C)[C@H]1C(=O)O
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a three necked 100 ml flask a suspension of trans-2,6,6-trimethyl-3-cyclohexene-1-carboxylic acid obtained in example 2 a) (0.800 g, 4.8 mmol), ethylbromide (0.616 g, 5.7 mmol) and K2CO3 (0.787 g, 5.7 mmol) in DMF (20 ml) was stirred at 40° C. for 2 h. The cooled reaction mixture was next poured onto cold 5% aqueous HCl and extracted twice with pentane. The organic phases were washed (three times with H2O and brine), dried (Na2SO4), filtered and concentrated. A bulb-to-bulb distillation (100°/4 mbar) afforded 0.870 g of ethyl trans 2,6,6-trimethyl-3-cyclohexene-1-carboxylate in the form of a trans/cis=96:4 mixture (yield=84%).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O1CCCC1>[NH2:1][C:2](=[S:29])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCC(N)=O)ccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CCC(N)=S)ccn1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 152.7 %

Procedure:
Under argon atmosphere, tert-butyl N-[4-(3-amino-3-oxopropyl)-2-pyridyl]-carbamate (11.79 g, 44.44 mmol) dissolved in tetrahydrofuran (100 ml) was added with Lawesson's reagent (9 g, 22.22 mmol) and stirred at 70-80° C. for 30 minutes. After the reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform chloroform:methanol=20:1) to obtain 9.544 g (76%) of the title compound as pale yellow crystals.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH2:15][CH2:16][CH2:17][N:18]=2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1>CO.O>[F:3][C:4]1[CH:5]=[C:6]([CH:14]2[CH2:15][CH2:16][CH2:17][NH:18]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: Fc1cc2c(c(C3=NCCC3)c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1cc2c(c(C3CCCN3)c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH4 (0.25 g, 6.69 mmol) was added to a solution of 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,4-dihydro-2H-pyrrole (Int-55) (0.8 g, 3.34 mmol) in a mixture of MeOH and H2O (3:1, 20 mL) and was stirred at 25° C. for 2 h. Reaction mixture was quenched with 1N aqueous HCl solution (50 mL) and basified with 2N aqueous NaOH solution to pH 8 and extracted with DCM (3×20 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine (Int-56). MS (ESI) m/z 224.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CC2)c(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC3CC3)c(F)cc2Cl)CC1
Yield: 43 %

Procedure:
0.335 g (0.75 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.242 g (0.83 mmol) 2-chloro-4-fluoro-5-[(cyclopropylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.231 g obtained (43% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.47 (br, 1H), 7.72-7.92 (m, 2H), 7.33-7.51 (m, 3H), 7.20-7.28 (m, 2H), 7.01-7.16 (m, 3H), 4.45-4.57 (m, 1H), 4.06-4.12 (m, 1H), 3.87-3.98 (m, 1H), 3.21-3.42 (m, 6H), 2.97-3.10 (m, 1H), 2.44 (s, 3H), 2.23-2.42 (m, 2H), 1.95-2.17 (m, 2H), 1.72-1.92 (m, 8H), 1.55-1.65 (m, 2H), 0.34-0.53 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[NH2:37])[CH2:21][CH2:20]1.Cl.O1CCOCC1>CO>[N:22]1([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[NH:37][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=2[CH3:18])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-3-methyl-2-phenylquinoline (150 mg, 591 μmol), 2,5-dimorpholinobenzenamine (156 mg, 591 μmol) and 4N hydrochloric acid solution in dioxane (0.15 mL, 591 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.18 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.6, 1.2 Hz), 7.69 (1H, td, J=7.6, 1.2 Hz), 7.59-7.66 (2H, m), 7.41-7.57 (4H, m), 7.23 (1H, s), 7.12 (1H, d, J=8.6 Hz), 6.44 (1H, dd, J=8.6, 2.7 Hz), 6.04 (1H, d, J=2.7 Hz), 3.88-4.01 (4H, m), 3.69-3.80 (4H, m), 3.02-3.16 (4H, m), 2.88-3.00 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=481.3 (M+1).
Reaction SMILES: C1O[C:4]2([CH:8](OS(C)(=O)=O)[CH2:7][C:6]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[N:5]2[CH3:20])[O:3]C1.[I-].[Na+]>CC(C)=O>[CH3:20][N:5]1[C:6]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:7][CH2:8][C:4]1=[O:3]
Reactant: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN1C(=O)CCC12CCC(=O)CC2
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mL) was refluxed with stirring for 90 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water. After drying over magnesium sulfate the solvent was removed in vacuo. The residue was dissolved in toluene (20 mL) and treated with tri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resulting mixture was heated at 110° C. for 1 h. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. The resulting product was stirred with a mixture of water (5 mL), 3N HCl (1.5 mL) and acetic acid (2 mL) for 16 h. The resulting product was extracted 3 times with methylene chloride, washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvent was removed in vacuo to afford 1 -Methyl-1-azaspiro[4.5]decane-2,8-dione as an oil.
Reaction SMILES: CC1N=C(N[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])SC=1C1C=CN=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[S:32][C:31]([NH2:33])=[N:30][C:29]=2[CH3:34])[CH:25]=[C:24]([CH3:35])[N:23]=1>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[S:32][C:31]([NH:33][C:14]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[O:15])=[N:30][C:29]=2[CH3:34])[CH:25]=[C:24]([CH3:35])[N:23]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Reactant: Cc1cc(-c2sc(N)nc2C)cc(C)n1
Product: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1

Procedure:
The titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine with 5-(2,6-Dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH3:17])=[N:11][CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:10]([O:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH3:17])=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)C(C)Oc1ncncc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1ncncc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, 10% palladium/carbon and ethyl acetate is stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system is purged with nitrogen, then, the reaction solution is filtrated through Celite, and the filtrate is concentrated to obtain 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:19])([O-:9])=[O:8].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:20]([O:19][C:11]1[C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:13][C:12]1[CH:16]=[CH:17][CH:18]=[CH:10][CH:11]=1)=[O:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 162.3 %

Procedure:
Potassium carbonate (16.6 g, 120.1 mmol) was added to a solution of 3-nitrosalicylic acid (10 g, 54.6 mmol) in DMF (100 ml) and benzyl bromide (14.3 ml, 120.1 mmol) was dropped thereinto. The mixture was stirred at 80° C. for 12 hours and the reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 16.1 g (yield 81%) of benzyl 2-benzyloxy-3-nitrobenzoate as brown oil.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:29]([CH3:40])[CH:28]=1)[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=2[N:16]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.ClCCl.C(O)C.ClCl>ClCCl>[NH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:29]([CH3:40])[CH:28]=1)[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=2[N:16]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: C[Si](C)(C)I
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 94 from N-[(1S)-3-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and iodotrimethylsilane in dichloromethane. Yield: quantitative; Rf value: 0.25 (silica gel; dichloromethane/ethanol=4:1); C23H26ClN5O2 (439.94); mass spectrum: (M+H)+=440/442 (chlorine isotope).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:28][NH:29][CH3:30]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH2:2][N:29]([CH3:30])[CH3:28])[CH:27]=[CH:26][CH:25]=2)[S:8]1(=[O:24])=[O:23]
Reactant: CNC
Reactant: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Product: CN(C)Cc1cccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)c1
Yield: 39 %

Procedure:
In an analogous manner to general procedure V, 1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.07 g, 0.18 mmol) was treated with dimethylamine (10 mL) to provide 0.03 g (39%) of 1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N,N-dimethylmethanamine. HRMS: calcd for C22H22FN3O2S+H+, 412.14895; found (ESI, [M+H]+), 412.1493; HPLC purity 96.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].C=O.[BH3-][C:43]#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][N:30]([CH3:43])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in methanol was added formalin (5 equiv.) stirred it at room temperature for 10 min. Then NaBH3CN (1 equiv.) was added to it Resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (195 yield). LCMS: 546.40 (M+1)+; HPLC: 94.91% (@ 254 nm) (Rt;7.295); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.84 (bs, 1H), 8.30 (d, 1H, J=2 Hz), 7.84 (d, 1H, J=9.2 Hz), 6.90 (s, 1H), 5.89 (s, 1H), 5.20 (m, 1H), 4.38 (d, 2H, J=4 Hz), 4.33 (bs, 1H), 4.19 (bs, 1H), 3.72 (bs, 2H), 2.90-2.65 (m, 5H), 2.20 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.91 (m, 1H), 1.80-1.70 (m, 3H), 1.61 (m, 1H), 1.50 (d, 6H, J=6 Hz), 1.28 (m, 1H).