Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@H:6]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH2:9][CH2:8][C@H:7]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])(=O)=O.[Li+].[B-](CC)(CC)CC.CCOC(C)=O.CCCCCC>C1COCC1>[F:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C@@H:7]1[CH2:8][CH2:9][C@@H:10]([O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[CH2:6]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](OS(C)(=O)=O)c2cccnc21)(C(C)C)C(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 21 flask was (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl methanesulfonate (55.2 g, 105 mmol) (azeotroped with dry benzene) in THF (300 mL) to give a tan solution. Superhydride (525 mL, 525 mmol) (1.0M in THF) was added dropwise via dropping funnel under nitrogen, and the mixture was stirred at rt for 4 h. THF was stripped off and the tan oil was partitioned between water (300 ml) and EtOAc (400 ml). The layers were separated and the organic layer was washed with brine, dried and concentrated to a tan oil (close to 60 g). Purification by FCC (2.5 L packed column) up to 30% EtOAc/hexane did not give good purification but did get rid of baseline (not very uv active) junk (use just a silica plug and <10% EtOAc/hexane should be ok too). All the collected less polar fractions were combined and concentrated to a tan oil (33.58 g) and was directly used in the next step. MS (ESI)[M+H+]=432.19.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29](=[O:30])[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: O=C(CCl)N1CCCCC1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCCCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 2-chloro-1-piperidin-1-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:22])([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH3:21])=[CH:13]2)[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:22][C:2]([F:1])([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH3:21])=[CH:13]2)[C:3]([OH:5])=[O:4]
Reactant: COc1cnc2ccc(C(F)(F)C(=O)OC(C)(C)C)cc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.2 %

Procedure:
A 200 mL round bottom flask was charged with tert-butyl 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate (5.06 g, 16 mmol) then CH2Cl2, then trifluoroacetic acid (16 ml, 213 mmol) followed by triethylsilane (6.5 ml, 41 mmol). The solution was maintained at rt for 24 h until LCMS showed disappearance of starting material. The solution was concentrated and was subjected to high vacuum for 40 h to give 4.1 g (99% yield) of 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid as a brown solid. The material was of sufficient purity for use in subsequent steps.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Br:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][C:51]=1[Cl:52]>C1COCC1>[Br:45][C:46]1[CH:47]=[C:48]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:49]=[N:50][C:51]=1[Cl:52]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of diethyl azodicarboxylate (1.52 mL, 9.6 mmol) in THF (56 mL) was added triphenylphosphine (2.52 g, 9.6 mmol) at 0° C., and the reaction mixture was stirred for half an hour. 1-BOC-2-(S)-azetidinemethanol (1.44 g, 7.7 mmol) and 5-bromo-6-chloropyridine-3-ol (1.4 g, 6.4 mmol; prepared according to V. Koch and S. Schnatterer, Synthesis 1990, 499-501)) were then added. The reaction mixture was slowly warmed up to room temperature overnight. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with CHCl3 :MeOH 100:1 to afford the title compound. MS (CI/NH3) m/z 377/379 (M+H)+.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.[I:11]N1C(=O)CCC1=O>C(#N)C>[I:11][C:7]1[C:8]([OH:10])=[C:9]2[S:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccnc2ccsc12
Solvent: CC#N
Product: Oc1c(I)cnc2ccsc12

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (from Aldrich) (0.54 g, 3.6 mmol) and N-iodosuccinimide (0.88 g, 3.9 mmol) in acetonitrile (10 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give the desired product which was used in the next step without further purification. LCMS calculated for C7H5INOS (M+H)+: m/z=277.9. Found: 277.8.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15]C[O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].B(Br)(Br)Br.[OH-].[K+]>O>[OH:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:17]([OH:19])=[O:18])[C:6]2=[O:16]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(O)c(O)cc21
Yield: 84.1 %

Procedure:
1.4-Dihydro-1-ethyl-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid (3.9 g) and boron tribromide (15 ml) were heated at 50° C. for 15 hours. The reaction mixture was cooled and added slowly to water (100 ml) at 0° C. The pH was adjusted to 11 with concentrated potassium hydroxide, the mixture was filtered and the filtrate taken to pH1, whereupon the precipitate was collected by filtration, washed with water and dried to give 1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinoline-3-carboxylic acid (3.13 g); δ((CD3)2SO) 1.42(3H,t); 4.46(2H,q); 7.23(1H,s); 7.66(1H,s); 8.82(1H,s)ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][O:5][C:4]1=[S:9])[CH3:2].[C:10]1([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[CH:21][C:19]2[O:20][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[O:5][C:4]1=[S:9])[CH3:2]
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: CCN1C(=O)COC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN1C(=O)C(=Cc2ccc(-c3ccccc3)o2)OC1=S
Yield: 45 %

Procedure:
To a mixture of 3-ethyl-2-thioxooxazolidin-4-one 3 (145 mg, 1.0 mmol), 5-phenyl-2-furaldehyde 4 (172 mg, 1.0 mmol) and sodium acetate (410 mg, 5.0 mmol) was added acetic acid (5 mL). The reaction mixture was refluxed for 30 h, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. The desired product 5 (JL101) was obtained by recrystallization from an ethyl acetate/hexanes mixture in 45% yield (135 mg, light yellow needles). 1H NMR (400 MHz, CDCl3): 7.81-7.76 (m, 2H), 7.44 (dt, J=8.0, 1.6 Hz), 7.36 (t, J=6.0 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H), 6.80 (s, 1H), 3.97 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](I)[CH3:29]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH3:29]
Reactant: CCI
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and ethyl iodide, white powdery N-[2-(4-difluoromethoxy-3-ethoxyphenyl)-oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:19](=[O:21])[CH3:20])=[CH:5][C:4]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc(N)cc1OCOCC[Si](C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(NC(C)=O)cc1OCOCC[Si](C)(C)C

Procedure:
A mixture of Example 476B, acetic anhydride (20 mL), and 4-(dimethylamino)pyridine (722 mg, 5.9 mmol) in dichloroethane (150 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was diluted with hexanes and stirred vigorously until a solid formed. The solid was filtered, rinsed with hexane, and dried under vacuum to produce 15 g (81% over 3 steps from Examples 476A-C) of the desired product. MS (ESI) m/e 334 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) □ 9.74 (s, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.18 (dd, J=2.5, 8.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.13 (s, 2H), 3.67-3.73 (m, 2H), 3.71 (s, 3H), 1.98 (s, 3H), 0.86-0.92 (m, 2H), -0.02 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O>CN(C=O)C>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH3:26])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1cnccc1B(O)O
Solvent: CN(C)C=O
Product: Cc1cnccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-methylpyridine-4-boronic acid (CAS RN 894808-72-1) and using DMF as solvent for the reaction. Colorless solid (13%). MS (ESI): m/z=440.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([I:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.N1C2C=CC=C(O)C=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][C:6]2[C:5]([I:12])=[CH:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[CH:7]=2)[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(I)c(CC(=O)O)cc1F
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5-fluoro-2-iodo-4-(methoxycarbonyl)phenyl)acetic acid (100 mg, 0.30 mmol), 1-benzhydrylpiperazine (82 mg, 0.33 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol), 1H-benzo[d][1,2,3]triazol-4-ol (61 mg, 0.45 mmol) and triethylamine (91 mg, 0.90 mmol) in DCM (5.0 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (20 mL), washed with HCl (2M, 10 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (60%-70% CH3CN in 0.1% HCOOH) to afford methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate (70 mg, 41%) as a white solid. LCMS (ESI): m/z: 572.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]([C:16]([Cl:20])=[C:17]([Cl:19])[Cl:18])=[C:13](Cl)[Cl:14])([O-:11])=[O:10].CO>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]([Cl:14])=[C:12]([N+:9]([O-:11])=[O:10])[C:16]([Cl:20])=[C:17]([Cl:18])[Cl:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=[N+]([O-])C(=C(Cl)Cl)C(Cl)=C(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(SC(Cl)=C(C(Cl)=C(Cl)Cl)[N+](=O)[O-])cc1
Reaction time: 20 h

Procedure:
At room temperature, 4.72 g (38 mmol) of 4-methylthiophenol are added to a solution of 10.00 g (36.9 mmol) of 2-nitropentachloro-1,3-butadiene in 20 ml of ether, and the mixture is stirred for 20 h. The ether is then removed under reduced pressure, and the crystal slurry which is formed after addition of 20 ml of methanol is filtered off, washed with cold MeOH (2×10 ml) and dried under reduced pressure, yield 9.9 g (75%), Rf=0.72 (Et2O: petroleum ether=1:3), m.p. 110-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 92.2 %

Procedure:
Hydrogenate a mixture of 3,5-difluorocinnamic acid (10.0 g, 54.3 mmol), 5% palladium on carbon (1.5 g), and concentrated sulfuric acid (10 ml) in tetrahydrofuran (195 ml) at 60 psi at room temperature overnight. After filtering the catalyst, dilute with ether, wash with water twice, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as clear colorless crystals (9.32 g, 92%). NMR (400 MHz, CDCl3): δ 2.67 (t, 2H), 2.94 (t, 2H), 6.65 (t, 1H), 6.74 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6C(OC(C)(C)C)=O)[NH:21][C:20]=5[CH:36]=4)=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:44](=[O:45])[C@@H:43]([NH:42][C:40](=[O:41])[O:39][CH3:38])[CH:47]([CH3:49])[CH3:48])[NH:21][C:20]=5[CH:36]=4)=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1)C(C)C
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of (S)-tert-butyl 2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (582 mg, 1.1 mmol), 4M HCl solution in dioxanes (5 mL, 20 mmol) and methanol (3 mL) was stirred at room temperature for twenty minutes. The reaction was concentrated, suspended in dichloromethane, and thoroughly concentrated. This crude amine was dissolved in dimethylformamide (5 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (281 mg, 1.6 mmol), HATU (691 mg, 1.8 mmol) and diisopropylethylamine (0.65 mL, 3.7 mmol). The reaction was stirred at room temperature for fifteen minutes, and then diluted ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield Methyl (S)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (376 mg, 58%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH:7]([Cl:6])[CH3:8])=[CH:10][CH:11]=1)=[O:14]
Reactant: c1ccsc1
Reactant: CC(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred and cooled (0° C) mixture of 4.2 parts of thiophene, 13 parts of stannic chloride and 40 parts of methylene chloride is added dropwise a solution of 10.2 parts of p-(1-chloroethyl)benzoyl chloride in 20 parts of methylene chloride (exothermic reaction with gaseous hydrogen chloride evolution). After stirring for 2h.30 the reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid solution. The product is extracted with methylene chloride. The organic layer is separated, washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleumether. The product is filtered off and crystallized from ethanol, yielding p-(1-chloroethyl)phenyl 2-thienyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([NH:17][NH2:18])=[O:16]>C(O)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[N:18][NH:17][C:15](=[O:16])[C:14]2[CH:19]=[CH:20][CH:21]=[C:12]([CH3:11])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: O=Cc1cccc(Cl)c1O
Solvent: CCO
Product: Cc1cccc(C(=O)NN=Cc2cccc(Cl)c2O)c1
Temperature: 60 °C
Yield: 24.9 %

Procedure:
A suspension of 3-chloro-2-hydroxy-benzaldehyde (0.100 g, 0.639 mmol) and 3-methyl-benzoic acid hydrazide (0.096 g, 0.639 mmol) in ethanol (2 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-methyl-benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-methylidene]-hydrazide as a white solid (0.046 g, 25%): mp 166-169° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=12.0 Hz, 1H), 7.76 (d, J=10.0 Hz, 2H), 7.47 (dd, J=15.6, 6.2 Hz, 4H), 6.97 (t, J=7.8 Hz, 1H), 2.39 (d, J=12.0 Hz, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: [F:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([Li])CCC.[C:17]1(=[N:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:20][CH2:19][CH2:18]1>O1CCCC1>[F:1][CH:2]([S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[C:17]1([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:18][CH2:19][CH2:20]1
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: CC(C)(C)S(=O)N=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(C(F)S(=O)(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.2 %

Procedure:
To a stirred solution of ((fluoromethyl)sulfonyl)benzene (5.0 g, 28.7 mmol) in tetrahydrofuran (100 mL) at −78° C. under argon was added n-butyl lithium (18.0 mL, 28.7 mmol) and the reaction mixture was stirred for 40 minutes at this temperature. N-cyclobutylidene-2-methylpropane-2-sulfinamide (3.23 g, 18.7 mmol) was added to the mixture at −78° C. and the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water and extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford a brown oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate, 3:2 to 2:3) to give N-(1-(fluoro(phenylsulfonyl)methyl)cyclobutyl)-2-methylpropane-2-sulfinamide (3.00 g, 33%) as a yellow oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].N[C:20]([NH2:22])=O.[NH2:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26](C)[CH3:27].N>>[NH2:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:20][NH2:22]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: NC(N)=O
Agent: N
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 30 °C
Reaction time: 24 h

Procedure:
The seed strain is inoculated in a 2 l-Erlenmeyer flask containing 300 ml of the same seed medium as in Example 1 and cultured with shaking at 30° C. for 24 hours. Then, 2 l of the resulting seed culture is put into a 30 l-jar fermenter containing 10 l of a fermentation medium comprising 100 g/l of blackstrap molasses (as glucose), 0.3 g/l of MgSO4.7H2O, 0.7 g/l of KH2PO4, 3 g/l of urea, 18 g/l of soybean meal acid hydrolyzate (as soybean meal) and 1.4% (v/v) of a leucine fermentation liquor prepared in advance as hereinafter described, and cultured at an aeration rate of 10 l/minute, a stirring speed of 400 r.p.m. and 30° C., for 48 hours, while adjusting pH of culture liquor at 6.8 with 22% aqueous ammonia. As a result, 43 g/l of L-lysine is formed and accumulated in the culture liquor. When a parent strain P-3634 is cultured in the same manner as above, 37 g/l of L-lysine is obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([OH:20])[CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.ClCCl>[Br:1][C:2]1[C:10]2[C:9]([N:19]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([OH:20])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: OC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: OC1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 100 %

Procedure:
5-Bromo-4-chlorothieno[2,3-d]pyrimidine (2.11 g, 8.5 mmol) in dry acetonitrile (100 mL) was treated with 8-azabicyclo[3.2.1]octan3-ol (1.34 g, 10.6 mmol) and potassium carbonate (3.519 g, 25.5 mmol) and stirred and heated at reflux for 4 h. The reaction was diluted with ethyl acetate (200 mL) and dichloromethane (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol as a yellow solid (2.890 g, 8.5 mmol, 100%). This was used directly in the next step without further purification. 1H NMR (CDCl3) δ: 1.83 (2H, d, J=12 Hz), 2.0 (2H, br s) 2.28 (2H, d, J=6 Hz), 2.45 (2H, d, J=8 Hz), 4.15 (1H, br s), 4.7 (2H, br s), 7.35 (1H, s), 8.45 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[C:13]1([C:11]2[NH:10][C:7]3=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]3[N:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccccc3)nc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Temperature: 80 °C

Procedure:
12.0 g 6-nitro-2-phenyl-3H-imidazo[4,5-b]pyridine were dissolved in 1 l acetic acid. 18 g iron powder were added and the mixture heated to 80° C. with stirring. After 2 hrs the mixture was cooled to room temperature and filtered over Celite. The celite pad was washed with methanol and the combined filtrates were evaporated. The residue was dissolved methanol/dichloromethane 1:1 and filtered over silica. The filtrate was concentrated to a volume of 100 ml, the resulting precipitate collected by filtration and washed with methanol. Yield 7.68 g