Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH3:13])=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22]>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:3]([NH:4][CH2:5][CH3:6])[N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH3:13])=[N:8]1)(=[O:23])=[O:22]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CCN=C(SC)N1CCC(CC)=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccccc1Cl)N1CCC(CC)=N1
Yield: 0.6 %

Procedure:
1.42 g (1 mol equiv.) 3,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 1.43 g (1.05 mol equiv.) 2-chlorobenzenesulfonamide were added to 20 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue obtained after purification by flash chromatography on silica gel (Et2O) was triturated with diisopropyl ether to afford 2.08 g (81%) 2-chloro-N-[ethylamino-(3-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-benzenesulfonamide. 1HNMR (400 MHz, CDCl3) δ 1.15 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.3 Hz, 3H), 2.38 (q, J=7.3 Hz, 2H), 2.80 (t, J=9.8 Hz, 2H), 3.44-3.53 (m, 2H), 4.11 (t, J=9.8 Hz, 2H), 6.73 (br.s., 1H), 7.33 (dt, J=7.6, 2.0 Hz, 1H), 7.38 (dt, J=7.6, 2.0 Hz, 1H), 7.46 (dd, J=7.6, 2.0 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:17](OC(=O)CC)(=O)[CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH2:18][CH3:19])=[CH:10][CH:11]=1)#[N:16]
Reactant: CCC(=O)OC(=O)CC
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc2cnccc2n1-c1ccc(C#N)cc1
Yield: 21.6 %

Procedure:
A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (Preparation 26(b)) (2.00 g, 9.5 mmol) and propionic anhydride (12.2 ml, 95 mmol) were heated together under nitrogen at reflux for 17 hours. The resulting solution was treated with excess aqueous sodium bicarbonate and the product was extracted into dichloromethane (3×150 ml). The combined extracts were dried (MgSO4), concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution with ethyl acetate/methanol) to give the title compound as a brown solid (510 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>ClCCl>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]1[O:32][CH2:31][CH2:30][O:17]1
Reactant: Cc1nc(C=O)c(Cl)n1-c1ccc(C#N)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C2OCCO2)c(Cl)n1-c1ccc(C#N)cc1
Reaction time: 70 h

Procedure:
A stirred solution of the aldehyde from (c) (0.24 g, lmmol) and 4-toluenesulphonic acid hydrate (0.21 g, 1.1 mmol) and ethane-1,2-diol (0.5 ml, 8 mmol) in dichloromethane (8 ml) was heated at reflux through a Dean-Stark trap containing 4A molecular sieves for 6 hours. After standing at 25° C. for 70 hours the mixture was washed with aqueous sodium bicarbonate and evaporated to a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[BrH:20].OO>>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: Br
Reactant: CCCCC(CC)COC(=O)c1cccc(C)c1N
Agent: OO
Product: CCCCC(CC)COC(=O)c1cc(Br)cc(C)c1N
Yield: 98.6 %

Procedure:
The above-described method (Example 1) was repeated to react 2-ethylhexyl 2-amino-3-methylbenzoate (3.00 g, 10.6 mmol) with hydrogen bromide (2.33 g, 13 8 mmol, 48% in water) and hydrogen peroxide (1.81 g, 15.9 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, 2-ethylhexyl 2-amino-5-bromo-3-methylbenzoate (2.7 g, 74.0% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Sn](C)C.C[Sn](C)C.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH:21]=[N:20][C:19]=1[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[F:36]>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>[F:36][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:30]=1[C:19]1[N:20]=[CH:21][C:22]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])=[N:23][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: O=C(Nc1cnc(-c2ccncc2F)c(Cl)n1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cnc(-c2ccncc2F)c(-c2ccc(F)cn2)n1)C1CC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
An oven dried resealable Schlenk tube was charged with 2-bromo-5-fluoropyridine (0.52 g, 2.9 mmol), hexamethylditin (0.97 g, 2.9 mmol) and toluene (15 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (0.162 g, 0.14 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 80° C. After 5 hours, the mixture was cooled and N-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (Preparation 10, 0.424 g, 1.45 mmol) and further tetrakis(triphenylphosphine)palladium (0.162 g, 0.14 mmol) were added. The mixture was heated to 110° C. and stirred overnight. The mixture was concentrated, ethyl acetate was added and the organic solution was washed with 4% aqueous sodium bicarbonate solution, brine, dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 98:2). The appropriate fractions were concentrated to leave a solid which, upon washing with a mixture of hexane and ethyl acetate, gave the title compound (0.077 g, 15%) as an off-white solid.
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C([Mg]Cl)(C)(C)C.Cl[P:26]([NH:35][C@H:36]([C:38]([O:40][CH:41]([CH2:46][CH2:47][CH3:48])[CH2:42][CH2:43][CH2:44][CH3:45])=[O:39])[CH3:37])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[CH3:37][C@H:36]([NH:35][P:26]([O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[C@:2]([CH3:1])([OH:18])[C@@H:6]1[OH:7])=[O:27])[C:38](=[O:39])[O:40][CH:41]([CH2:46][CH2:47][CH3:48])[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: CCCCC(CCC)OC(=O)[C@H](C)NP(=O)(Cl)Oc1ccccc1
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(CCC)OC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@](C)(O)[C@@H]1O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2′-C-Methylcytidine was diluted with THF (0.097 M). The resulting slurry was cooled to −78° C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0° C., stirred for 30 min and again cooled to −78° C., then propylpentyl N-[chloro(phenyloxy)phosphoryl]-L-alaninate (as 1.0 M solution in THF, 2.2 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried over Na2SO4. The crude product was purified by column chromatography on silica gel (DCM/MeOH 92:8), and the resulting off white solid was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O, water buffered with 5 mM AMBIC). Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as a white solid.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([O:31]CC2C=CC=CC=2)[C:25]([O:39]CC2C=CC=CC=2)=[CH:24]3)[CH:13]=[C:12]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]>[Pd].C1COCC1>[C:7]([CH2:6][N:5]([C:10]1[CH:11]=[C:12]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([OH:31])[C:25]([OH:39])=[CH:24]3)[CH:15]=1)[CH2:4][C:1]([OH:3])=[O:2])([OH:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(O)c(O)cc3c2)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A mixture of 1.16 g of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine and 0.35 g of 10% palladium on carbon in 75 ml of THF was stirred under a hydrogen atmosphere until uptake ceased after 6 hours. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated to a solid which was triturated with hexane and filtered to give 0.835 g (90% yield, mp 153°-155°) of N-(carboxymethyl)-N-[3-[4-(2,3-dihydroxy-6-naphthalenyl)butoxy]-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:16])([F:15])[CH2:10][S:11](Cl)(=[O:13])=[O:12].[F:17][C:18]([F:53])([F:52])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[O:28][CH:29]=[C:30]([CH2:32][O:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[CH:47][N:46]=[C:45]4[CH2:49][CH2:50][NH2:51])=[CH:36][CH:35]=3)[N:31]=2)=[CH:21][CH:20]=1.O>C1COCC1>[F:8][C:9]([F:16])([F:15])[CH2:10][S:11]([NH:51][CH2:50][CH2:49][C:45]1[N:44]([CH2:43][CH2:42][CH2:41][CH2:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[N:31]=[C:27](/[CH:26]=[CH:25]/[C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:53])([F:52])[F:17])=[CH:24][CH:23]=4)[O:28][CH:29]=3)=[CH:35][CH:36]=2)[CH:48]=[CH:47][N:46]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(CC(F)(F)F)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 1.83 h

Procedure:
Triethylamine (137 μl) and 2,2,2-trifluoroethanesulfonyl chloride (65.0 l) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (250 mg) in THF (5 ml) at 0° C., and the mixture was stirred at the same temperature for 110 min. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex) (eluent; hexane:ethyl acetate=1:2 to 1:4) and recrystallized from ethyl acetate-methanol-hexane to give the titled compound (48 mg) as colorless needle crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]([C:22]([OH:24])=O)=[C:12]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#N.N1C=CC=CC=1>C(COC)OC>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[C:19](=[O:21])[O:20][C:22](=[O:24])[C:13]3=[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:11]=2[CH:10]=1
Reactant: O=C(O)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O
Agent: N#N
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1

Procedure:
Acetic anhydride (288 μl, 3.0 mmol) was added to a stirred suspension of 6-chloro-4-phenylquinoline-2,3-dicarboxylic acid (100 mg, 0.31 mmol) in dimethoxyethane (1 ml) in an inert N2 atmosphere followed by the addition of pyridine (49 μl, 0.61 mmol) at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8 Hz), 7.45-7.55 (m, 3H), 7.67 (m, 2H), 7.83 (m, 2H), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 443.9 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][NH:29][CH3:30])[CH:9]=1
Reactant: CNC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1j (60 mg, 0.11 mmol) was dissolved in 8 mL of dichloromethane, followed by addition of 2 mL of trifluoracetic acid, and then the reaction solution was stirred for 1 h. 20 mL of saturated sodium bicarbonate solution was added, and the reaction solution was extracted with dichloromethane (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide 1 (15 mg, a yellow oil), and the yield of the three steps was 16%.
Reaction SMILES: C([N:8]([CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19](=[O:21])[NH2:20])[CH:13]=1)C1C=CC=CC=1.C(O)C>CO.[Pd]>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][CH2:10][CH2:9][NH:8][CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[NH2:20]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)c2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NC(=O)c1cc(OCCNCC(O)c2ccccc2)ccc1O

Procedure:
Analogously to Example 4, a solution of 45 g of crude α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]benzyl alcohol in 500 ml of methanol is hydrogenated with the addition of 5 g of palladium-on-charcoal catalyst (5%) and the reaction mixture is worked up. α-[N-[2-(3-Carbamoyl-4-hydroxy-phenoxy)-ethyl]aminomethyl]-benzyl alcohol with a melting point of 174°-175° (from ethanol) is obtained. The methanesulfonate melts at 182°-183° (from methanol).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[NH:43][CH:42]=[CH:41][C:38]3=[N:39][CH:40]=2)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]3[N:3]=[C:2]([C:35]4[CH:36]=[C:37]5[NH:43][CH:42]=[CH:41][C:38]5=[N:39][CH:40]=4)[N:11]=[CH:10][C:9]2=3)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cnc5cc[nH]c5c4)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 50 mg, 0.127 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (61.8 mg, 0.253 mmol) and PdCl2(dppf) (4.63 mg, 6.33 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.03-3.18 (m, 1H), 3.18-3.30 (m, 5H), 3.73-3.87 (m, 2H), 3.92-4.19 (m, 3H), 4.59-4.81 (m, 3H), 6.76-6.97 (m, 1H), 7.53-7.77 (m, 2H), 7.86-8.08 (m, 2H), 8.14-8.33 (m, 1H), 8.96-9.20 (m, 1H), 9.26-9.42 (m, 1H), 12.40-12.69 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C24H24N6O3S, 477.16. found 477.2.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]1.C[O-].[Na+].CO.Cl>O>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]2([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]2)=[O:7])[N:9]=1)#[N:27]
Reactant: NCC1(C(=O)O)CCC1
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(OC3CCCCC3)cc12
Yield: 35.2 %

Procedure:
A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (20 mg, 0.054 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid (37 mg, 0.22 mmol) in 0.5 M NaOMe/MeOH solution (0.84 mL, 0.42 mmol) was microwaved at 120° C. for 2 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 8 mg (0.019 mmol) in 35% yield. LC-MS ESI−: 422.03 (M−1)−.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@H:29]1[NH:34][C@@H:33]([CH3:35])[CH2:32][N:31]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[C@H:33]([CH3:35])[CH2:32][N:31]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: [OH:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9](=[O:17])[CH2:10][NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[OH:8]>[Pt]=O.CO>[CH3:16][C:12]([NH:11][CH2:10][CH:9]([C:4]1[C:3]([O:18][CH3:19])=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=1)[OH:17])([CH3:15])[CH2:13][CH3:14]
Reactant: CCC(C)(C)NCC(=O)c1ccc(O)c(O)c1OC
Agent: O=[Pt]
Solvent: CO
Product: CCC(C)(C)NCC(O)c1ccc(O)c(O)c1OC

Procedure:
6.5 g of 1-(3,4-dihydroxy-2-methoxyphenyl)-2-(1,1-dimethylpropylamino)ethanone are hydrogenated with 0.1 g of platinum oxide as catalyst in 125 mL of methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, the precipitated crystals are suction filtered and washed with ethyl acetate and diethyl ether. Yield: 5.5 g (85%; benzoate); melting point: 172° C.-174° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30]([O:32]CC)=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Temperature: 0 °C
Yield: 89 %

Procedure:
Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (4.01 mmol, 1.8 g) was dissolved in ethanol (20 ml) and cooled to 0° C. NaOH 2 M solution (8.03 mmol, 4.01 ml) was added and the mixture was stirred at RT for an hour. The mixture was heated to 60° C. and stirred for 10 h. Ethanol was evaporated and the residue was diluted with water. The pH was adjusted to 4 with 1 M HCl solution which precipitated the product. The precipitate was removed by filtration and washed with water. The solid was dried under vacuum. 1.5 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 6.75 (bs, 1H), 7.08-7.17 (m, 6H), 7.18-7.34 (m, 5H), 7.36-7.49 (m, 8H). LC-MS: [M−1]=419.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:34]I>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:20]=3)(=[O:17])=[O:18])[CH3:34])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
Starting with [(R)-4-(3-methanesulfonyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 5-1) and methyl iodide using the method analogous to the one described for example 2-1, {(R)-4-[(3-methanesulfonyl-5-trifluoromethyl-benzene-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester was obtained MS cald. for C20H24F3N3O6S2 523, obsd. (ESI+) [(M+H)+]: 524.