Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])=[O:9].C(N(CC)C(C1C=CC=CC=1S([C:43]1[C@H:44]([CH3:74])[C@@H:45]2[C@@H:62]([C@H:63]([O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[CH3:64])[C:61](=[O:73])[N:46]2[C:47]=1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49])=O)=O)C.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([S:15][C:43]2[C@H:44]([CH3:74])[C@@H:45]3[C@@H:62]([C@H:63]([O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:67])[CH3:68])[CH3:64])[C:61](=[O:73])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=2)=[O:49])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:17])=[O:9]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
75 μl of a hexane solution containing 1.6M of butyllithium was added to 1 ml of an ice-cooled toluene solution containing 18 μl (0.13 mmol) of diisopropylamine, and the mixture was stirred for 10 minutes. At the end of this time, 125 μl (0.12 mmol) of a hexane solution containing 0.97M of diethylaluminium chloride was added and the mixture was stirred for a further 20 minutes ac this temperature. The diethylaluminium diisopropylamide solution thus obtained was added to 2 ml of an ice-cooled tetrahydrofuran solution containing 43 mg (0.12 mol) of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine, and stirred for 15 minutes at this temperature. At the end of this time, 1 ml of a tetrahydrofuran solution containing 68 mg (0.10 mmol) of 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) was added to the reaction mixture, and the mixture was stirred for 105 minutes. A saturated aqueous solution of ammonium chloride and then ethyl acetate were added, and the precipitate which formed was removed. The organic layer was separated, and washed with water and then with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 10 g of silica gel, using a 1:3 by volume mixture of benzene and ethyl acetate as the eluent, to obtain 60 mg of a fraction containing the title compound in a yield of 74%. This fraction showed a purity of 56% as determined by the area ratio according to liquid chromatography.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-difluoro-phenyl)-acetic acid methyl ester (1.20 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionic acid methyl ester (1.79 g, quant.) as a clear oil: EI-HRMS m/e calcd for C15H18F2O2 (M+) 268.1275, found 268.1278.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(trifluoromethyl)phenol (4.86 g, 1 equiv), 4-fluorobenzaldehyde (3.22 mL, 1 equiv), potassium carbonate (4.15 g, 1 equiv) and dimethylformamide (60 mL) was stirred at 150° C. under argon for 3 hours, then poured into ice/water. The precipitate was filtered off, washed with water, then extracted with hot ethanol. Undisolved solid was removed by filitration, and the filtrate evaporated and purified by chromatography on silica. 1H-NMR (CDCl3) δ 7.14 (4H, m), 7.66 (2H, m), 7.90 (2H, m), 9.97 (1H, s); MS (APCI+). found (M+1)=267; C14H9F3O2, requires 266.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:42]2[CH2:43][CH:40]([O:39][CH3:38])[CH2:41]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COC1CNC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1N
Yield: 58.6 %

Procedure:
HATU (2.70 g, 7.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-chlorophenyl)ureido]phenylacetate (1.35 g, 76%) as a colorless powder. 1H-NMR (CDCl3) δ3.58 (s, 3H), 3.71 (s, 2H), 7.04 (m, 3H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.27-7.39 (m, 3H), 8.07 (m, 2H); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].C(NCC)C>C(#N)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]#[N:40])[CH:13]=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccccc1CBr
Solvent: CCNCC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCc1cncn1Cc1ccccc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-trityl-1H-imidazole (2.10 g, 4.48 mmol) in acetonitrile (20 mL) is added 2-bromomethylbenzonitrile (0.967 g, 4.93 mmol). The reaction mixture is stirred at 60° C. for 16 h. It is then cooled to room temperature and diethylamine (5 mL, 44.8 mmol) is added. The reaction mixture is stirred at 60° C. for 30 min. It is then cooled to room temperature and the solvents are removed in vacuo. Methanol (25 mL) is added and stirring is continued for 1 h at room temperature. Methanol is removed by concentration in vacuo. The residue is dissolved in ethyl acetate and washed with water twice. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-{5-[2-(tert-butyldimethylsilanyloxy)-ethyl]-imidazol-1-ylmethyl}-benzonitrile; MS (ESI) m/z 342 (M+H)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:27])[C:16]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:18]([C:19](OC)=[O:20])[CH:17]=1>C(Cl)(Cl)Cl>[O:20]=[C:19]1[C:18]2[CH:17]=[C:16]([C:15]([O:14][CH3:13])=[O:27])[CH:25]=[CH:24][C:23]=2[N:26]=[C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:7]12
Reactant: CCOC(=O)c1ccc(Cl)nn1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2nc3ccc(C(=O)OC)cc3c(=O)n2n1

Procedure:
A mixture of ethyl 6-chloro-3-pyridazinecarboxylate (0.29 g, 1.55 mmol, Example 1, Step A) and dimethyl 4-aminoisophthalate (0.36 g, 1.72 mmol, Example 1, Step B) was heated as a melt at 165°-170° C. for 30 min. The oil was dissolved into chloroform, washed with 10% ammonium hydroxide solution, dried (MgSO4) , filtered and concentrated. Medium pressure chromatography (silica gel, chloroform to 1% methanol in chloroform) of the crude oily-solid afforded 2-ethyl 8-methyl 10-oxo-10H-pyridazino[6,1-b]quinazoline-2,8-dicarboxylate as a yellow solid, mp 218°-221° C. dec.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(C=P(CCCC)(CCCC)CCCC)#N.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: Sc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSc2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene was added cyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and benzenethiol (121 μL, 1.21 mmol) at RT. The mixture was heated to 110° C. for 2 h. The reaction was cooled down, quenched (sat. aq. NH4Cl solution), extracted (2×EtOAc), and washed with brine. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc/hexane) provided the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([N+:20]([O-])=O)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C:11]1[CH:12]=[C:13]([NH2:20])[CH:14]=[C:15]([NH2:17])[CH:16]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCOC(=O)c1cc(N)cc(N)c1
Temperature: 7 °C
Reaction time: 1.67 h

Procedure:
9 g of 5% palladium carbon, 90 g (0.27 mol) of 2-(3,5-dinitrobenzoyloxy)ethyl isobutyrate (compound 3) and 900 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was increased to 5 kg/cm2. The autoclave contents were stirred at room temperature (7° C.). 10 minutes later, the autoclave inside temperature rose to 34° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Ten minutes later, the temperature became 50° C. and the pressure dropped to 1 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (4 kg/cm2), stirring was continued for 100 minutes (the temperature dropped to 18° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from 200 ml of toluene to obtain 2-(3,5-diaminobenzoyloxy)ethyl isobutyrate (compound 4). Yield: 60 g (83%) Melting point: 81-83° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](O)(=[O:26])/[CH:21]=[CH:22]\[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]3=[O:26])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)C=CC1=O)OC2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.53 g, 1.86 mmol, prepared as described in Example 17) in tetrahydrofuran (10 ml) was added, maleic acid (0.24 g, 2.05 mmol) and diisopropylcarbodiimide (0.58 ml, 3.72 mmol). The reaction mixture was heated to reflux for 3 h. and then allowed to cool to room temperature over an 18 hours period. The solvent was stripped off in vacuo and the residue diluted into ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (2×50 ml), 1% hydrochloric acid (2×20 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo affording an oil which was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (6:4) as eluent. Pure fractions (Rf=0.25) were collected and the solvent evaporated in vacuo to give 0.60 g (90%) of 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16].O>CCO>[N:11]1[C:10]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cnc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc2[nH]cnc12
Temperature: 25 °C

Procedure:
Benzimidazole ester 3 (1.65 g, 9.36 mmol), hydrazine monohydrate (10 mL), and water (3 mL) were refluxed in EtOH (60 mL) for 24 hs. Reaction mixture was cooled to room temperature and solid formed was filtered, washed with EtOH and dried to give 1.13 g (68%) of pure 4: 1H NMR (DMSO-d6) δ 12.31 (br.s, 1H), 10.59 (s, 1H), 8.44 (s, 1H), 7.86 (d, 1H, J=6.5 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.34 (t, 1H, J=8.0 Hz), 4.68 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-methoxypyridin-4-ylboronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 1 tR=1.9 min, m/z=447 (M+1); 1H NMR (CDCl3) 8.29 (1H, d, J=5.5 Hz), 7.34 (2H, m), 7.21-7.15 (m, 3H), 7.02-6.93 (5H, m), 5.67-5.61 (1H, m), 4.05 (3H, s), 3.53 (1H, t, J=6.41 Hz), 2.97-2.93 (1H, m), 2.33-2.11 (3H, m), 2.06-1.83 (3H, m), 1.67-1.57 (1H, m), 1.50 (3H, d, J=7.03), 1.36-1.26 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:42]([CH2:47][CH:48]1[CH2:50][O:49]1)[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)C>[CH2:31]([N:42]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:47][CH:48]([OH:49])[CH2:50][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCN(CC1CO1)S(C)(=O)=O
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCCCCCCCCCCN(CC(O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1)S(C)(=O)=O

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 6.11 g (20 mmol) of N-undecyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2c), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([S:11]([CH3:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([C:5]1[CH:10]=[C:9]([S:11]([CH3:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([NH2:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)C)cc1S(C)=O

Procedure:
15.5 g 5-tert-butyl-1-methanesulphinyl-2-methoxy-3-nitro-benzene in 300 ml of ethyl acetate are added 3.0 g 10% palladium-(II)-hydroxide on charcoal and the mixture is hydrogenated for 16 hours at 3 bar hydrogen pressure. Then the hydrogenation catalyst is filtered off through kieselguhr and washed with 100 ml of ethyl acetate. The solvent is eliminated in vacuo and the residue is extracted from n-pentane.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:5]([NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride was added dropwise to a solution of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.44 g) in pyridine (4.4 ml). After being stirred for two hours at ambient temperature, the mixture was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole. The residue was converted to the hydrochloride in a usual manner and the salt was recrystallized from a mixture of methanol and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (0.43 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Si](C)(C)C)=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[Br:26]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:26])=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1Cl
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)c(F)c(N)c1Cl
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (0.240 g, 0.617 mmol) in CH2Cl2 (2.469 mL) at 20° C. was added bromine (0.127 mL, 2.469 mmol). After 24 h, the reaction mixture was poured into a saturated aqueous solution of Na2S2O3 and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound as a white solid (0.187 g, 0.473 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: NCc1cc(C2CC2)no1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1cc(C2CC2)no1)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and 3-cyclopropyl-5-isoxazolemethanamine (CAN 851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 99.6%, 452.2 (M+H)+.