Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH:42]=[CH2:43])[C:32]1=[O:33])[CH:29]=[CH2:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH:29]=[CH2:30])[C:32]1=[O:33])[CH:42]=[CH2:43]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(C(C)(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[OH:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][CH:31]=1
Reactant: Cn1cc(I)ccc1=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1cc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)ccc1=O

Procedure:
Prepared according to the method described in Example 7c) from 5-iodo-N-methylpyridin-2-one (Example 13a), 0.276 g), ethanol (4 ml), toluene (10 ml), 2M aqueous sodium carbonate (0.58 ml), (2R)-4-[2-(tert-butyldimethylsilanyloxy)-4-pyridin-3-yl-butoxy]benzeneboronic acid (Example 7b), 0.471 g), and tetrakis(triphenylphosphine)palladium(0) (0.03 g). After work up, the residue was purified by column chromatography over silica eluting dichloromethane:methanol (95:5) to give the title compound as a foam (0.191 g).
Reaction SMILES: [CH2:1]([O:17][C:18]1[C:19](=[O:32])[CH:20]=[C:21]([CH2:24][O:25]C2CCCCO2)[O:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.CCCCCC>C1COCC1.CCOCC>[OH:25][CH2:24][C:21]1[O:22][CH:23]=[C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:19](=[O:32])[CH:20]=1
Reactant: CCCCCCCCCCCCCCCCOc1coc(COC2CCCCO2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Yield: 96 %

Procedure:
A solution of 5-hexadecyloxy-2-tetrahydro pyranyloxymethyl-4-pyrone (1.1 g, 2.5 mmol) and HCl (10% in H2O, 10 ml) in THF (30 ml) was stirred at 25° overnight. TLC (ETAC/hexane: 3/7) indicated reaction was complete. The solution was diluted with ether (200 ml), washed with H2O (3×50 ml), 10% NaHCO3 (1×50 ml), sat'd NaCl (1×100 ml), dried (K2CO3) and concentrated to provide 0.88 g (98%) of 2-hydroxymethyl-5-hexadecyloxy-4-pyrone as a pure white solid mp 68.0°-69.5°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:16]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[N+]=[N-].CO.[ClH:31].CCOCC>C1COCC1.[Pd].C(Cl)Cl.CCCCCC>[C:19]1([S:16]([C:11]2[C:10]3[C:14](=[CH:15][C:7]([O:6][CH2:5][CH2:4][NH2:1])=[CH:8][CH:9]=3)[NH:13][N:12]=2)(=[O:17])=[O:18])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[ClH:31]
Reactant: [N-]=[N+]=NCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: NCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 6-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (0.17 g, 0.45 mmoles) and 10% Pd/C in THF (2 mL), and methanol (8 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was recrystallized from CH2Cl2/hexane, 1M HCl in ether (0.4 mL, 0.4 mmoles) was added, then dried, to afford the title compound as an off-white HCl salt (0.15 g, 0.4 mmoles), MS: (ES+) 368 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH2:25])[NH:18][N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:33]([C:35]1[O:36][C:37](=[O:60])[C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]3[O:55][C:54]([CH3:57])([CH3:56])[C:53]([CH3:59])([CH3:58])[O:52]3)[CH:46]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:34].Cl>CN(C=O)C.CCOC(C)=O>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:33]([C:35]3[O:36][C:37](=[O:60])[C:38]4[C:43]([C:44]=3[C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]5[O:52][C:53]([CH3:59])([CH3:58])[C:54]([CH3:57])([CH3:56])[O:55]5)[CH:46]=3)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH3:34])[N:17]=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[C:24]=12
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
In a 100 ml round bottomed flask 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 400 mg, 1,194 mmol) was dissolved in 7 ml of dry DMF then K2CO3 (254 mg, 1.837 mmol) was added. After stirring for 5 min a solution of 3-(1-bromoethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (Intermediate C26, 420 mg, 0,918 mmol) in 7 ml of dry DMF was added and the clear brown mixture was heated at 60° C. for 30 min. The mixture was cooled to r.t. then 30 ml of HCl 0.5 M and 50 ml of EtOAc were added and stirred for 15 min. Phases were separated and the crude material was purified by chromatography eluting with DCM\MeOH (80/20) in DCM to give the title compound (820 mg) as a brown oil. This material was used in the next step without any further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:25])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:24])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.CCOC(C)=O>[OH:8][CH2:9][C@@H:10]([CH3:25])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:24]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Yield: 89.5 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF32) (4.03 g, 12.0 mmol) and tetrabutylammonium flouride monohydrate (4.46 g, 16.0 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF34) (2.70 g, 100%). 1H NMR (CDCl3) δ 6.91 (d, J=8.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.54 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.57 (s, 2H), 4.19 (dd, J=9.4 Hz, J=14.6 Hz, 1H), 3.78 (s, 3H), 3.56-3.39 (m, 3H), 2.84 (s, 1H), 2.09-1.99 (m, 1H), 1.05 (d, J=7.2 Hz, 3H); 13C NMR (CDCl3) 165.8, 155.5, 139.5, 129.4, 117.4, 107.7, 103.0, 67.7, 63.8, 56.0, 43.6, 34.1, 15.0.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.C1(COC(=O)[CH2:24][CH2:25][C@H:26]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][C:28]([O:30]C)=O)C=CC=CC=1.Cl.[H][H]>CCCCCC.O1CCCC1.ClCCl.C(O)C.[Pd]>[CH3:39][C:36]([O:35][C:33](=[O:34])[NH:32][C@H:26]1[CH2:25][CH2:24][C:28](=[O:30])[CH2:27]1)([CH3:37])[CH3:38]
Reactant: [H][H]
Reactant: COC(=O)C[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCC(=O)C1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
2.5M n-Butyllithium in hexane (5.83 ml) was added dropwise to a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (3.16 ml, 15 mmol) in tetrahydrofuran (30 ml) at 4° C. After 20 min the solution was cooled to -60° C. and (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-hexanedioic acid 1-methyl 6-(phenylmethyl) ester (1.522 g, 4.16 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min. The solution was stirred for 10 min before the addition of pH7 buffer (5 ml) and the mixture was then diluted with dichloromethane (200 ml) and pH7 buffer (300 ml). The aqueous phase was adjusted to pH6.5 with 2M hydrochloric acid and then the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×200 ml) and the combined organic phase was dried (MgSO4) then evaporated to leave a solid. The solid was dissolved in ethanol (45 ml) and hydrogenated over 10% palladium-on-carbon (0.5 g) for 4 h. The hydrogen was replaced by nitrogen and the reaction was stirred for a further 18 h then filtered through celite and the pad was washed with ethanol. The filtrate and washings were combined and evaporated to leave a solid which was purified by column chromatography on flash silica eluting with 25-40% ethyl acetate in cyclohexane to give the title compound (0.437 g) as a white solid which crystallised from isopropyl ether, m.p. 97°-98° C., [α]D -48° (CHCl3 c=0.52%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C@@H:15]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20]1)=[O:17]>>[CH2:24]([N:21]1[CH2:22][CH2:23][C@H:19]([NH:18][C:16](=[O:17])[C@@H:15]([NH:14][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Product: CC(C)(C)[C@H](NC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
Compound 3b was prepared from 3-(trifluoromethyl)phenyl isocyanate and compound 2b, using the method described in Example 9. MS (EI)=476 (M+).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:14]([O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]([O:23]CC=C)=[O:22])=[CH:19][N:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([SnH](CCCC)CCCC)CCC.Cl>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[C:14]([O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C=CCOC(=O)c1ccc(OC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Agent: [Pd]
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)Oc2ccc(C(=O)O)cn2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
100 mg of this ester were dissolved in 5 ml of absolute tetrahydrofuran and treated under argon with 104 mg of tetrakis-(triphenylphosphine)-palladium and 61 mg of tributyltin hydride. After stirring at room temperature for 30 min., the reaction mixture was poured on to ice/saturated ammonium chloride solution, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The dark oil obtained after drying and evaporation was purified by chromatography (RP18-LiChroprep, acetonitrile) and recrystallization from ethyl acetate. There were obtained 21 mg of 6-[3-adamantan-1-yl-4-(tert-butyl-dimethyl-silanyloxy)-benzoyloxy]-nicotinic acid in colorless crystals, m.p. 188°-190° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][C:18]=3[C:28]([F:31])([F:30])[F:29])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][C:18]=3[C:28]([F:29])([F:31])[F:30])(=[O:15])=[O:16])[CH2:11][N:10]2[C:32](=[O:34])[CH3:33])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)CN2)CC1
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccc(-n3cccn3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(4-pyrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide from experiment D9 was acylated with acetic anhydride in analogy to experiment L29 to give (2S,4R)-1-acetyl-4-(4-pyrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.3 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[N:12]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.CO.C1(C)C=CC=CC=1>[Pd]>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[N:12]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(C3CC3)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1)c(-c1ccnc(C3CC3)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
3-(2-Cyclopropyl-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole (2 gm) was dissolved in 20 mol of 50% methanol/toluene and balloon hydrogenated for 18 hrs in the presence of 0.4 gm of 50% by weight 10% Pd/C. The reaction mixture was filtered and evaporated to give the title product.
Reaction SMILES: O[N:2]=[C:3]([NH2:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[OH:23][CH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH2:24])=[NH:2])=[CH:9][CH:8]=2)[CH2:19][CH2:18]1
Reactant: NC(=NO)c1ccc(OCCCC2CCN(CCCO)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCC2CCN(CCCO)CC2)cc1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To an acetic acid (50 mL) suspension of 4.58 g of N′-hydroxy-4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzamidine was added 2.59 mL of acetic anhydride at room temperature, which was then stirred at the same temperature for one hour. To the reaction mixture was added 0.50 g of 5% palladium-carbon, which was then stirred at room temperature under hydrogen atmosphere for 5 hours and 30 minutes. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Water was added to the resultant residue, which was adjusted to pH 12.5 using a 5 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water to provide 4.82 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:2]2[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: FC(F)(F)Oc1cccnc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1cccnc1C1CC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
A solution of 2-bromo-3-(trifluoromethoxy)pyridine (Preparation 247, 776 mg, 3.21 mmol), cyclopropyl boronic acid (331 mg, 3.85 mmol) and potassium phosphate tribasic (1.70 g, 8.02 mmol) in toluene (10 mL) and water (3 mL) was degassed with nitrogen for 15 minutes at 80° C. Palladium acetate (36 mg, 0.16 mmol) and tricyclohexyl phosphine (90 mg, 0.32 mmol) were added and the reaction mixture was vigorously stirred for 18 hours at 95° C. under nitrogen. The solution was concentrated in vacuo, diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10% diethyl ether in heptane to afford the title compound as a colourless oil (292 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]=[S:12]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:11]([NH:10][C:13](=[O:14])[O:15][CH2:16][CH3:17])=[S:12])=[N:7][CH:8]=1
Reactant: COc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Yield: 62.3 %

Procedure:
In the same manner as in Reference Example 30 and using 5-methoxypyridin-2-amine (1.05 g, 8.43 mmol), DMSO (5 mL) and ethyl isothiocyanatoformate (1.44 g, 11.0 mmol) as starting materials, the title compound (1.34 g, 62%) was obtained as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[N:15]=[C:14]([O:16][C:17]3[C:22]4[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>C(O)CCC.[OH-].[Pd+2].[OH-]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:15]=[C:14]([O:16][C:17]3[C:22]4[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=3)[N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCN(C(C)C)CC4)n3)cccc2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCCCO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4CCN(C(C)C)CC4)n3)cccc2s1
Temperature: 120 °C

Procedure:
To a mixture of N-(4-(2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (100 mg, 0.18 mmol, Example 28), HCO2N44 (227 mg, 3.6 mmol, Aldrich) in butanol (2 mL) was added palladium hydroxide (8.3 mg, 0.016 mmol, 20 wt. % Pd (dry basis) on carbon, Aldrich), and the mixture was heated to 120° C. for 16 h with stirring under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through Celite® pad. The filter cake was washed with MeOH and the combined filtrates were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (7% MeOH/DCM) to provide the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 556 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][OH:13]>C1COCC1.O(C)[K]>[CH3:12][O:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CO
Agent: CO[K]
Solvent: C1CCOC1
Product: COc1cc(O)ccc1[N+](=O)[O-]

Procedure:
To a solution of 3-Fluoro-4-nitro-phenol (15.7 g, 100 mmol) in THF (300 mL), 30% KOMe in Methanol (49 mL, 210 mmol) is added at 0° C. The mixture is heated to gentle reflux for 18 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and 4-(methylsulfonyl)phenylboronic acid was prepared the title compound as a mixture of E and Z isomers (2:1) as a white solid, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH3:30])[C:22]([S:26]([NH:8][C:9]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10]2)(=[O:27])=[O:28])=[C:23]([CH3:25])[CH:24]=1
Reactant: COC(=O)C1(N)CCC1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2c(C)cc(OC)cc2C)CCC1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
Triethylamine (13.9 mmol, 2.0 equiv.) was added at 0° C. to a solution of methyl 1-aminocyclobutanecarboxylate (6.97 mmol, 1 equiv.) in dichloromethane p.a. (20 ml), and the mixture was stirred for 10 minutes. 4-Methoxy-2,6-dimethyl-phenylsulfonyl chloride (8.36 mmol, 1.2 equiv.), dissolved in DCM (5 ml), was slowly added dropwise at the same temperature, and the mixture was stirred for 4 hours at 25° C. The reaction mixture was diluted with dichloromethane (100 ml), washed with distilled water (2×50 ml) and saturated sodium chloride solution (2×50 ml) and dried over sodium sulfate. The solvent was concentrated and the crude product was purified by column chromatography (15% ethyl acetate in hexane) to yield the desired product in the form of a white solid. Yield: 66%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:9]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo aniline (5 g, 29 mmol), benzaldehyde (3.24 ml, 32 mmol) and acetic acid (2.49 ml, 44 mmol) in dry tetrahydrofuran (50 ml) was stirred at room temperature for 3 hrs. Sodium borohydride (2.755 g, 73 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (100 ml) and extracted with dichloromethane (3×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 263 (M+H)