Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH4-].[Na+]>C1COCC1.C(O)(C)(C)C>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a suspension of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl 2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) in THF:t-butanol (1:1) (10 mL) was added NaBH4 (0.46 g, 12.4 mmol). The reaction stirred at room temperature under argon overnight. The reaction mixture was quenched with acetic acid (2 mL) and the solvent was removed in vacuo. The residue was triturated with water and filtered. The solid was washed with fresh water followed by ethanol. The solid was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired compound (1.58 g, 44%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, 1H), 8.56 (s, 1H), 7.52 (m, 1H), 7.01 (m, 2H), 6.55 (m, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.71 (2H), 2.54 (s, 3H); ES-HRMS m/z 408.0940 (M+H calculated for C19H17N3O3ClF2 requires 408.0921).
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:25])[CH2:4][CH2:3]2.[CH3:26]I>>[CH3:26][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:25]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(S(=O)(=O)c3ccccc3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(S(=O)(=O)c4ccccc4)cc3CC[C@@H]12

Procedure:
A 200 mg portion of (4aR)-(10bR)-10b-methyl-8-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated with methyl iodide to obtain 144 mg of the desired product. mp 165°-167° FDMS: m/e=369. α[D]589 =+76.2, α[D]365 =+269.7 (chloroform).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17](O)=[O:18])[CH2:12][CH2:11]3)=[O:5].[CH2:29]([NH2:31])[CH3:30].N>>[CH2:29]([NH:31][C:17]([C:16]1[C:15]2[CH2:14][CH:13]3[O:20][CH:10]([CH2:11][CH2:12]3)[C:9]=2[S:8][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:21]([C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=[CH:24][C:2]=1[F:1])=[O:18])[CH3:30]
Reactant: CCN
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Agent: N
Product: CCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 4A and ethylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])[CH:6]=[CH:5][C:4]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].CCO.Cl>O>[OH:27][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OS(=O)(=O)c4ccc(C)cc4)c(OC)c2)CC3)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(O)c(OC)c2)CC3)cc1
Yield: 88.2 %

Procedure:
Combine toluene-4-sulfonic acid 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-phenyl ester (1.029 g, 1.92 mmol) and KOH (2.15 g, 38.48 mmol) with EtOH (30 mL) and water (20 mL). Reflux the reaction for 10 h and dilute with water (50 mL). Acidify with 5.0 M HCl (8 mL). Remove the organic solvent in vacuo and dilute the residue with water (10 mL). Collect the solid material by filtration and wash with water (3×10 mL) and Et2O (2×15 mL) then dry in a vacuum oven to give 0.646 g (88%) of the title compound. MS/ES m/z 382.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][CH2:14][CH3:15])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]2[NH:21][C:22](=[O:24])[S:23][C:19]=2[CH:18]=1>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:16][C:17]3[C:26]([O:27][CH3:28])=[CH:25][C:20]4[NH:21][C:22](=[O:24])[S:23][C:19]=4[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]=1[CH2:13][CH2:14][CH3:15])[CH3:12]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCCc1[nH]c2ncnc(Cl)c2c1CC
Product: CCCc1[nH]c2ncnc(Nc3cc4sc(=O)[nH]c4cc3OC)c2c1CC

Procedure:
100 mg (447 μmol) 4-chloro-5-ethyl-6-propyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 22a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 3.2 mg (2%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1>CCCCCC.C(O)C>[CH3:1][N:2]1[C:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1O
Solvent: CCO
Solvent: CCCCCC
Product: Cn1nccc1[C@@H]1CCCC[C@H]1O

Procedure:
The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol prepared in Example 4a was optically resolved with CHIRALPAK IB (Daicel Corp.; hexane/ethanol=9:1) to yield the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[S:32]
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Fc1cccc(F)c1C(=S)NNc1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure described in Example 58, by treating 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide (see Examples 35 and 36) with Lawesson reagent there is produced 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-thiobenzhydrazide which is required as the starting material in Example 18.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:34])(=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=C(C=C(S(=O)(=O)N(C)C)C=1OC1C=CC=CC=1)C(OCC)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:34])(=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)OCC)cc(NCc2ccccc2)c1Oc1ccccc1
Agent: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)N(C)C)c1
Product: CCCCNS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1

Procedure:
By substituting in step B above ethyl 3-benzylamino-5-(n-butylsulphamyl)-4-phenoxy-benzoate for the ethyl 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate, and after recrystallization from ethanol, the aove compound was obtained with a melting point of 212°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[N+:7]([O-])=[C:8]([CH3:10])[CH:9]=1)([O-])=O.C.C(O)(=O)C>CO>[NH2:1][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:12])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N)cc(C)n1
Reaction time: 10 h
Yield: 122.8 %

Procedure:
A mixture of 4-Nitro-2,6-lutidine 1-oxide (21, 5.1 g, 30 mmol), palladized charcoal (10% Pd, 1 g) and acetic acid (2 ml) in methanol (200 ml) is hydrogenated under pressure (40 psi) over 10 hours using a hydrogenation apparatus. The reaction is followed with LC-MS. After filtration, the filtrate is concentrated. The remaining oil is further dried by lyophilization, yielding 4.5 g of 4-amino-2,6-lutidine (22) containing approximately 15% acetic acid. 1H NMR (300 MHz, CDCl3) δ 2.3 (s, 6H), 7.2 (s, 2H). MS, m/z 123 (M+1), 243 (2M−1).
Reaction SMILES: CSC.B.[CH3:5][N:6]([CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH:7]([CH3:9])[CH3:8].CO.Cl>C1COCC1>[CH3:5][N:6]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)N(C)Cc1ccc(C#N)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)N(C)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
Under a nitrogen atmosphere, add borane-dimethyl sulfide complex (8.7 mL, 17.4 mmol, 2M solution in THF) to a solution of 4-[(N-methyl-iso-propylamino)-methyl]-benzonitrile (660 mg, 3.51 mmol) in THF (20 mL) at room temperature then heat to reflux for 30 min. Cool the mixture in an ice-bath and carefully add methanol (10 mL). Warm the mixture to room temperature and add concentrated HCl (10 mL). Stir the mixture for 12 h, and concentrate in vacuo. Purify by chromatography on silica gel (25 g) eluting with a gradient of DCM to 1:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound (550 mg, 82%). MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Oc2ncccn2)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (3.4 g), 2-chloropyrimidine (2.29 g) and potassium carbonate (3.04 g) in dimethylsulfoxide (30 ml) was stirred at 150° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give methyl 3-(pyrimidine-2-yl)oxybenzoate (3.66 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:16]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC.O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([S:23][C:24](=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])[N:18]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CSc1nc(OC)cc(OC)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(=Cc1ccccc1)Sc1nc(OC)cc(OC)n1
Reaction time: 0.17 h

Procedure:
2.8 g (28.7 mmol) Diisopropylamine was dissolved in 80 ml tetrahydrofuran under nitrogen and treated with 11.5 ml (28.7 mmol) 2.5M n-butyllithium in hexane at a temperature between -78° and -50° C. The mixture was stirred for 10 minutes and then a solution of 7 g (28.7 mmol) methyl 2-(4,6-dimethoxy-2-pyrimidinylthio)acetate in 80 ml tetrahydrofuran was added to the reaction mixture and the mixture then stirred for 20 minutes. 2.8 g (28.7 mmol) Benzaldehyde was added, dropwise, to the solution. The reaction mixture was slowly allowed to reach room temperature, with stirring, and then stirred for 16 hours. The precipitate was treated with 500 ml water and extracted with ethyl acetate. The ethyl acetate phase, after drying over magnesium sulphate, was evaporated and then purified by medium pressure chromatography using hexane/ethyl acetate as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][NH2:22])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](O)=[O:41])[CH:36]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:19]([NH:21][NH:22][C:40]([C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:39][CH2:38]3)=[O:41])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: CC(C)(C#N)c1cc(-c2cnc(N)c(C(=O)NN)n2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)NNC(=O)c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)ccc2C1

Procedure:
3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbohydrazide (49.5 mg, 0.1665 mmol), 2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (50.80 mg, 0.1832 mmol), diisopropyl ethyl amine (25.82 mg, 34.80 μL, 0.1998 mmol) and (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (58.82 mg, 0.1832 mmol) was stirred at ambient temperature in N,N-dimethyl formamide (495.0 μL) for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The combined organic extracts were washed with aqueous saturated sodium bicarbonate, then 0.5 N hydrochloric acid, followed by brine. The organic extracts were then dried over MgSO4 and concentrated in vacuo to give the sub-titled product. (92 mg, 99.27%) LC/MS m/z 557.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.[NH2:15]O.O>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]#[N:15]
Reactant: NO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.49 g of hydroxylamine hydrochloride in 5.0 ml of formic acid was refluxed for 1 h. 50 ml of water was added and the product was filtered and washed with water. Yield 0.3 g (33%), m.p. 175°-178° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]2[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCN(CCCN)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 483 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25]([CH3:26])=[O:38])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Solvent: ClCCl
Solvent: CO
Product: CCC(CCC#N)(c1ccc(Cl)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg (0.31 mmol) of the compound from Example 157 were introduced into 12 ml of dichloromethane at 0° C., 77 mg (0.31 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 120 mg (96% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]4[CH:18]=[CH:17][C:16]([C:19]5[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:29](=[O:39])[C@@H:30]([NH:34][C:35](=[O:38])[O:36][CH3:37])[CH:31]([CH3:33])[CH3:32])=[N:21][CH:20]=5)=[CH:15][C:11]4=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:40]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:65]1[NH:69][C:68]([C@@H:70]2[CH2:74][CH2:73][CH2:72][N:71]2[C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])=[N:67][CH:66]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].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.O.CS(C)=O>[CH3:37][O:36][C:35]([NH:34][C@@H:30]([CH:31]([CH3:32])[CH3:33])[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:22]1[NH:23][C:19]([C:16]2[CH:17]=[CH:18][C:10]3[C:11]([CH:15]=2)=[CH:12][CH:13]=[C:14]2[C:9]=3[O:8][CH2:7][C:6]3[CH:40]=[C:2]([C:65]4[NH:69][C:68]([C@@H:70]5[CH2:74][CH2:73][CH2:72][N:71]5[C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])=[N:67][CH:66]=4)[CH:3]=[CH:4][C:5]2=3)=[CH:20][N:21]=1)=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(Br)cc2CO4)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]3)cc2CO4)[nH]1)C(C)C
Temperature: 90 °C
Reaction time: 14 h
Yield: 24.8 %

Procedure:
A mixture of methyl (S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (466 mg, 0.77 mmol), bis(pinacolato)diboron (235 mg, 0.93 mmol) and potassium acetate (227 mg, 2.3 mmol) in dioxane (4 mL) was degassed with a stream of argon for fifteen minutes. To this mixture was added PdCl2(dppf) (56 mg, 0.08 mmol) and the reaction was heated to 90° C. After 14 hours, the mixture was cooled to room temperature. To the reaction was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (341 mg, 1.1 mmol), 2M aqueous potassium carbonate solution (1.54 mL, 3.1 mmol) and DMSO (3.9 mL). The reaction was degassed with a stream of argon for fifteen minutes. Tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.08 mmol) was added and the reaction was heated to 90° C. After 4.5 hours, the reaction was poured into water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]-chromen-8-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (145 mg, 25%).
Reaction SMILES: C(Cl)(Cl)Cl.C(O)C.[NH3:8].[CH3:9][C@H:10]([NH2:35])[CH:11]1[O:16][C@@H:15]([O:17][C@H:18]2[C@H:23]([OH:24])[C@H:22]([N:25](C(CN)=O)[CH3:26])[C@@H:21]([O:31][CH3:32])[C@@H:20]([OH:33])[C@@H:19]2[NH2:34])[CH2:14][CH2:13][CH2:12]1>CC(C)=O>[CH3:9][C@H:10]([NH2:35])[C:11]1[O:16][C@H:15]([O:17][C@H:18]2[C@H:23]([OH:24])[C@H:22]([NH:25][CH3:26])[C@@H:21]([O:31][CH3:32])[C@@H:20]([OH:33])[C@@H:19]2[NH2:34])[C@H:14]([NH2:8])[CH2:13][CH:12]=1
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2CCCC([C@H](C)N)O2)[C@H](O)[C@@H]1N(C)C(=O)CN
Reactant: N
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CN[C@H]1[C@@H](O)[C@H](O[C@H]2OC([C@H](C)N)=CC[C@H]2N)[C@@H](N)[C@H](O)[C@@H]1OC

Procedure:
The crude powders are then subjected to silica gel column chromatography using a mixed solvent of chloroform, ethanol, aqueous ammonia and acetone (2:2:1:2, by volume) as a developer. The crude powder containing Fortimicin factors B, KE and KG is suspended in the solvent and introduced into the column. Development is carried out with the same solvent at a flow rate of about 30 ml/hour. First, Fortimicin B and Fortimicin KE are eluted and then Fortimicin KG is eluted. The active fractions containing Fortimicin KG are collected and concentrated under reduced pressure. The concentrate is freeze-dried to obtain the free base of Fortimicin KG.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]([NH:19][NH2:20])=[NH:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](O)=O>>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:18]=[CH:21][NH:20][N:19]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=N)NN)sc1C(=O)NCc1ccccc1
Reactant: O=CO
Product: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
N-benzyl-5-(hydrazinyl(imino)methyl)-3-methylthiophene-2-carboxamide (0.65 g, 2.24 mmol) in formic acid (20 mL) was stirred at reflux for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then was concentrated in vacuo. The residue was dissolved in saturated aqueous sodium bicarbonate solution (50 mL) and extracted with 5% methanol in dichloromethane (3×75 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a light yellow solid (0.56 g, 84%): 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.48 (s, 1H), 7.39-7.30 (m, 5H), 6.14 (br s, 1H), 4.63 (d, J=5.4 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 299.2 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:36](=[O:38])[CH3:37]>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=4[C:36](=[O:38])[CH3:37])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)c1cc(C)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 95 °C
Yield: 46.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (2.87 g, 11.23 mmol), K2CO3 (2.5 g), 1-[2-(3bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C. for 6 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over MgSO4, then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% CH3OH:dichloromethane: 1,2 l; 3% CH3 OH:dichloromethane: 600 ml). The material thus obtained was crystallized from a small volume of ether and hexane to provide 2.13 g (46%) of off-white 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone, m.p.=92°-93° C.