Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][N:12]([CH2:20][CH:21]([OH:37])[CH2:22][O:23][C:24]2[C:29]3[C:30]4[C:35]([NH:36][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[CH:34][CH:33]=[CH:32][CH:31]=4)CC2C=CC=CC=2)=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:20][CH:21]([OH:37])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 47.5 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Benzyl carvedilol (205 g) obtained in step 3 was charged to ethyl acetate (2400 ml) and water (240 ml). The contents were stirred and 10% palladium on carbon (20 g) was added at room temperature. Hydrogen gas was bubbled at room temperature. The temperature was raised to 45-50° C. and bubbling was continued for 8 hours. The reaction mass was filtered to remove the catalyst and the filtrate was concentrated to remove solvent (about 2 L). The contents were chilled to 15-20° C., filtered and washed with chilled ethyl acetate (50 ml) to give carvedilol (140 g) (84%).
Reaction SMILES: [Na].[CH:2]([N:15]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:24][P:25](=[O:28])([CH3:27])[CH3:26]>CN(C)C=O>[CH:2]([N:15]1[C:19]([C:20]([O:22][CH2:24][P:25]([CH3:27])([CH3:26])=[O:28])=[O:21])=[CH:18][N:17]=[CH:16]1)([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CP(C)(=O)CCl
Reactant: O=C(O)c1cncn1C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CP(C)(=O)COC(=O)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
3.0 g (0.01 mol) of the sodium salt of 1-benzhydryl-5-imidazole-carboxylic acid (Example 11) and 1.8 g of chloromethyl dimethyl phosphine oxide were heated with 40 cc of dimethyl formamide to 120° C. under a nitrogen atmosphere until the reaction was completed. The solvent was removed under reduced presure and insoluble sodium chloride was separated by taking up the residue in acetone. Crystallization yielded colorless crystals melting at 174° C., Yield 3.2 g (88% of the theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:12])=[CH:9]/[CH2:10]O)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:15].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:9][CH3:10])[CH:12]=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C\CO)c1cccc(Br)c1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC=C(C=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (E)-3-(3-bromophenyl)-but-2-en-1-ol (1.03 g, 4.54 mmol) in DCM (10 mL) at 0 deg C., was added Dess-Martin periodinane (2.11 g, 5 mmol). The resulting suspension was warmed to 23° C. and stirred for approx. 30 min. until the reaction was complete by TLC. The mixture was poured into 50 mL of saturated aqueous NaHCO3, containing Na2S2O3 (1 g). This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a white solid (910 mg, 89% yield) that was a 5:1 ratio of E:Z isomers.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:9]1.Cl.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([N:10]3[CH2:9][CH2:8][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CNCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C1COCCN(C2CCC3(CC2)OCCO3)C1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Et3N (96.9 mL, 0.695 mol) was added in one portion to a stirred suspension of homomorpholine hydrochloride (79.76 g, 0.579 mol) and 1,4-dioxaspiro[4.5]decan-8-one (90.5 g, 0.579 mol) in 1,2-dichloroethane (1.81 L). Then glacial acetic acid (34.8 mL, 0.607 mol) was added in one portion followed by solid NaBH(OAc)3 (154 g, 0.727 mol) in one portion as well. This was accompanied by 5° C. increase in the temperature of the reaction mixture. After 2 h 45 min the reaction was quenched by addition of 10% aqueous NaOH (800 mL). The mixture was stirred for 10 min. The organic layer was separated, washed with brine (100 mL), dried (MgSO4) and concentrated to afford an oil (142.36 g) with some suspended solid, which was filtered off (3.00 g). The aqueous part of the reaction mixture was combined with the brine washings and extracted with EtOAc (4×500 mL). Combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to afford additional portion of oil (16.82 g). The two oily products were combined and distilled in vacuum to give 8 (101.07 g, 72%) as colorless liquid, b.p. 122° C./8.9·10−3 mbar. 1H NMR (400 MHz, CDCl3) δ 1.48-1.64 (m, 4H), 1.70-1.88 (m, 6H), 2.50-2.63 (m, 1H), 2.71-2.81 (m, 4H), 3.66-3.72 (m, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.93 (s, 4H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC(=[O:49])CCCC1C2C(=CC=CC=2)NC=1)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[NH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:49])[CH2:1]1
Reactant: O=C(CCCc1c[nH]c2ccccc12)NCc1ccccc1
Reactant: c1ccc(CNCCCCc2c[nH]c3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCCNC2

Procedure:
N-Benzyl-4-(3-indolyl)-butanamine. Lithium aluminum hydride (4.8 g) was added to a solution of N-benzyl-3-indolebutanamide (18.73 g) in dry THF (200 mL) at nitrogen atmosphere and at 0° C. After stirring at reflux for 15 h and work-up with sodium hydroxide the title compound was obtained as pale yellow crystals (16.4 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[C:7]([CH2:9][C:10]1([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)[CH2:13][NH:12][CH2:11]1)#[N:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([CH2:3][C:4]([N:12]1[CH2:13][C:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)([CH2:9][C:7]#[N:8])[CH2:11]1)=[O:6])#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanoacetic acid (3.1 mg, 0.036 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (11.9 mg, 0.0241 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.036 mmol) in N,N-dimethylformamide (0.6 mL), followed by triethylamine (10. μL, 0.072 mmol). The reaction mixture was stirred at r.t. for 1 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=563.2.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:29][CH2:30][CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][CH2:30][NH:29][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)NCCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow solid, MS (ESI+): m/z=418.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:8])([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)c1
Yield: 60 %

Procedure:
5-[4-(3-Nitrobenzamido)phenyl]-2(1H)-pyrazinone was reduced with cyclohexene and palladium on charcoal in ethanol in a manner similar to that described in Example 6 to give the title compound (60%) m.p.>250° C.; δ(DMSO-d6) 8.01 and 8.10 (2H, ABq, pyrazinone ring protons), ##STR15## ν(Nujol mull) 1525 (--NHCO), 1660 (C=0) cm-1.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:29][CH3:30])=[C:22](N)[CH:21]=2)=[C:14]([Br:32])[CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:29][CH3:30])=[C:22]([F:1])[CH:21]=2)=[C:14]([Br:32])[CH:13]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(N)c(OC)c(C(C)C)c2)c(Br)c1
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2cc(F)c(OC)c(C(C)C)c2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
A solution of nitrosonium tetrafluoroborate (121 mg, 1.03 mmol) in dichloromethane (10 mL) was cooled to 0° C. and methyl[3,5-dibromo-4-(3-amino-5-isopropyl-4-methoxy-phenoxy)phenyl]acetate (457 mg, 0.94 mmol) was added. The reaction mixture was stirred at 0° C. for one hour. Dichloromethane was removed by flushing of nitrogen gas and o-xylene (10 mL) was added to the residue. The reaction mixture was heated at reflux for one hour and the organic phase concentrated in vacuo. The residue was purified on column (silica gel, n-heptane/ethyl acetate, gradient elution from 98:2 to 60:40) to give 205 mg (44%) of methyl[3,5-dibromo-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)phenyl]acetate.
Reaction SMILES: Br.Cl.[Cl:3][CH2:4][CH2:5][NH2:6].[C:7]([NH:9][C:10](=[N:13][CH2:14]CCl)OC)#[N:8].CN>>[C:7]([NH:9][C:10]([NH:13][CH3:14])=[N:6][CH2:5][CH2:4][Cl:3])#[N:8]
Reactant: COC(=NCCCl)NC#N
Reactant: NCCCl
Agent: Br
Agent: CN
Agent: Cl
Product: CNC(=NCCCl)NC#N

Procedure:
Dimethyl-(N-cyanoimido)carbonate is a known compound. Its preparation was described e.g. in J. Org. Chem. 1974, 39, 1522. According to the process of Yugoslavian Application No. P-2151/83, dimethyl-(N-cyanoimido)carbonate is reacted with chloroethylamine hydrochloride hydrobromide to N-cyano-N'-(2-chloroethyl)-O-methyl-isourea, which is reacted with methylamine to yield the N-cyano-N'-methyl-N"-(2-chloroethyl)guanidine.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([Cl:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CO>>[ClH:26].[Cl:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2cccc3cncc(Cl)c23)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2cccc3cncc(Cl)c23)CC1
Yield: 225.3 %

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 92 (40.4 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (37.8 mg) as light yellow powdery solid.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:8](=[O:20])[O:7]1)(=O)C>CO.C1COCC1>[Si:13]([O:12][C@@H:10]1[CH2:11][C@@H:6]([CH2:5][OH:4])[O:7][C:8](=[O:20])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Temperature: 24 °C
Reaction time: 27 h
Yield: 54.2 %

Procedure:
(2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)methyl acetate (7) (8.36 g, 27.64 mmol) and [t-Bu2SnOH(Cl)]2 (1.577 g, 2.764 mmol) are dissolved in MeOH/THF mixture (280 mL). The reaction mixture is stirred at 23-25° C. for 27 h. The solvent is removed under reduced pressure and the remaining residue is purified by silica gel chromatography (elution with t-BuMeO/hexane mixture) to afford a crude product as white solid (5.59 g, 78%). Recrystallization from n-hexane affords (3.90 g, 54%) of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-tetrahydro-pyran-2-one (8) as white needles. M.p.=102° C. (DSC peak). 1H NMR (300 MHz, CDCl3) δ: 4.80 (m, 1H), 4.38 (m, 1H), 3.91 (dd, J=12 Hz, J=3 Hz, 1H), 3.66 (dd, J=12 Hz, J=5 Hz, 1H), 2.60 (d, J=4 Hz, 2H), 2.31 (bs, 1H), 1.97−1.75 (m, 2H), 0.88 (s, 9H), 0.09, 0.08 (2s, 6H). 13C NMR (75 MHz, CDCl3) δ: 170.1, 76.8, 64.7, 63.4, 39.2, 31.9, 25.6, 17.9, −4.9, −5.0.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 1-piperazinecarboxylate, 1 (0.74 g, 4 mmol), and 4-nitrobenzyl bromide, 2 (0.86 g, 4 mmol), in N,N-dimethylformamide (DMF, 5 mL) was added potassium carbonate (3 g), and the reaction mixture was stirred at room temperature for 4 h. The product was extracted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL×3). The solution was dried with sodium sulfate, and solvent was removed in vacuo. The product was purified by column chromatography, eluting with ethyl acetate to afford 3 as a solid (1.22 g, 95% yield), mp 99-100° C. 1H NMR (DMSO-d6): 8.21-8.19 (d, 2H, J=8.8 Hz, Ar-H), 7.61-7.59 (d, 2H, J=8.0 Hz, Ar-H), 3.63 (s, 2H, CH2), 3.34-3.30 (m, 4H, partially obscured, 2×CH2), 2.35-2.3 (m, 4H, 2×CH2), 1.39 (s, 9H, 3×CH3). Anal. (C16H23N3O4) C, H, N.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:18]1[O:21][CH:19]1[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1CO1
Reactant: COC(=O)c1ccc(CN2CCNCC2)cc1
Product: COC(=O)c1ccc(CN2CCN(CC(C)O)CC2)cc1
Yield: 63 %

Procedure:
This is prepared analogously to Example 11 from methyl 4-(piperazin-1-ylmethyl)-benzoate and propylene oxide. Yield 63% of theory; m.p. 63°-64° C.
Reaction SMILES: C([C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1)#N.FC1C(F)=CC=C[C:39]=1[S:45](C)(=[O:47])=[O:46]>>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:3]([S:45]([CH3:39])(=[O:47])=[O:46])[C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3C#N)c3nc(-c4ccccn4)[nH]c3c2)cn1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Product: CS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3S(C)(=O)=O)c3nc(-c4ccccn4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 438 (step 2) or in accordance with the method or by combining it with an ordinary method but using 4-hydroxy-6-(6-methanesulfonyl-pyridin-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole obtained in Example 447 and 2,3-difluoro-methanesulfonylbenzene.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution containing the product from Example 2C (0.074 g, 0.138 mmol) in THF (1.5 mL) was treated with the product from Example 124A (0.051 g, 0.152 mmol), DEPBT (0.062 g, 0.207 mmol), and N,N-diisopropylethylamine (0.120 mL, 0.691 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.066 g, 56% yield).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[CH2:9]=[O:10]>C1(C)C=CC=CC=1>[OH:10][CH2:9][N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2]
Reactant: C=O
Reactant: CCc1nc(C)c[nH]1
Solvent: Cc1ccccc1
Product: CCc1nc(C)cn1CO
Yield: 92.9 %

Procedure:
110 g of 2-ethyl-4-methylimidazole are dissolved in 400 ml of toluene at 50° C. 30 g of paraformaldehyde are introduced into this solution, whilst stirring. The mixture is then stirred for 16 hours at 50°-55° C. and is cooled in an icebath, and the crystal slurry is filtered off. The resulting crude product is recrystallized from 300 ml of acetone. 130 g of 1-hydroxymethyl-2-ethyl-4-methylimidazole (corresponding to a yield of 92.9% of theory), of melting point 83.1°-86.3° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](N)[S:8][C:4]=2[CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH2:14][O:15][C:16]3[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(Cl)cc3s2)c1F
Yield: 38 %

Procedure:
Synthesised from 6-chloro-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 38% (second step), mp 190-191° C., HPLC-MS (method 1): m/z 355 [M+H]+, Rt=3.85 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[N:5]=[CH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Clc1cc(-c2cccs2)ncn1
Solvent: CCO
Product: CN1CCN(c2cc(-c3cccs3)ncn2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-chloro-6-thiophen-2-yl-pyrimidine (48 mg, 0.24 mmol) in ethanol (3 mL), was added 1-methylpiperazine (0.54 mL, 0.49 mmol). The resulting mixture was heated at 100° C. in a sealed tube for 2 h. The resulting mixture was concentrated and the resulting crude residue was purified by SiO2 chromatography (0-5% 2 M NH3 in MeOH/CH2Cl2) to yield the title compound.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[S:19]1[CH:23]=[CH:22][C:21]([C:24]2C=C(CC=O)C=C[CH:29]=2)=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:2]=[C:3]([C:6]3[S:10][C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[N:8][CH:7]=3)[CH:4]=[CH:5][CH:29]=2)=[CH:20]1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: O=CCc1cccc(-c2ccsc2)c1
Product: Oc1ccc(Nc2ncc(-c3cccc(-c4ccsc4)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-thiophen-3-yl-phenyl)-acetaldehyde (Example 25). The title compound: ES-MS: 350.9 [M+H]+; single peak at tR=4.16 min (System 2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH2:19])([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)[CH3:2].Br.CN1CCOCC1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH:19][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:17])[CH3:18])[N:15]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2nc(C(C)(C)N)cs2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2nc(C(C)(C)NC(=O)c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-[4-(1-Amino-1-methyl-ethyl)-thiazol-2-yl]-benzoic acid ethyl ester:hydrobromide (11.0 mmol) and n-methylmorpholine (2.0 mmol) in dichloromethane (0.10M), add benzoyl chloride (1.0 mmol) diluted in 2 mL dichloromethane. Stir at room temperature for 20 minutes. Wash the reaction with water while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify via radial chromatography eluting with ethyl acetate and hexane. MS (m/e): 395.2 (M+H)+