Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][C:17]=3[F:29])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=1)=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][C:17]=3[F:29])[N:10]([CH2:32][C:33](=[O:34])[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(C(=O)N4CCCC4)cc3F)nc12
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(C(=O)N3CCCC3)cc1F)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 36 (ii) starting from 40.0 mg (0.10 mmol) 2-[2-Fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester and 29.2 mg (0.12 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a colorless amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].[Na+].[Cl-].C1C=CC=CC=1.CCCCCC>O1CCCC1>[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)c1ccccc1I
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1I)N1CCOCC1

Procedure:
A solution of 15 ml of morpholine in 30 ml of tetrahydrofuran was reacted with a solution of 8.0 g o-iodobenzoyl chloride in 20 ml tetrahydrofuran for 10 minutes. The product was obtained in the manner described in Example 3, using saturated NaCl instead of H2O. There was obtained by recrystallization from benzene/hexane 6.8 g of N-o-iodobenzoylmorpholine as hard, translucent crystals, m.p. 86°-87°, Rf 0.73.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M192) (216 mg, 0.396 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (37 mg, 22%).
Reaction SMILES: C[N:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:23]([NH:33][CH2:34][CH2:35][C:36]1C=CC(O)=[C:38]([OH:39])[CH:37]=1)(OCC1C=CC=CC=1)=O>C1C=CC=CC=1>[C:38]([C:7]1([OH:8])[C:9]([C:38](=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[N:33][CH:23]=2)([OH:10])[CH:11]=[CH:12][C:5]([CH2:4][CH2:3][NH:2][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:6]1)(=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[N:33][CH:23]=1
Reactant: CN(CCc1ccc(O)c(O)c1)C(=O)OCc1ccccc1
Reactant: O=C(NCCc1ccc(O)c(O)c1)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(NCCC1=CC(O)(C(=O)c2cccnc2)C(O)(C(=O)c2cccnc2)C=C1)OCc1ccccc1

Procedure:
By working as described in Example 1, but replacing the N-methyl-N-carbobenzoxy-dopamine with an equivalent amount of N-carbobenzoxy-dopamine, 3,4-dinicotinoyl-N-carbobenzoxy-dopamine is obtained (m.p. 86°-90° C., from benzene).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:16]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 50 °C

Procedure:
2,3,4-Trimethoxybenzoic acid (Aldrich) (20 g, 94 mmol) was dissolved in dry DMF (250 mL). K2CO3 (13 g, 94 mmol) and MeI (6.5 mL, 103.4 mmol) were added and the reaction mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to rt and water (250 mL) was added. EtOAc (1 L) was added and the organic phase was washed with water (3×500 mL) and finally with NaCl (sat.). The organic phase washed dried over MgSO4, filtered and concentrated in vacuo. Redissolved in toluene and evaporated. Methyl 2,3,4-trimethoxybenzoate was obtained as a slightly yellow oil. 1H NMR (CDCl3) δ=7.60 (1H, d), 6.70 (1H, d), 3.99 (3H, s), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s). Yield 21 g (99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>ClCCl.CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]4[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=4)=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)=[O:16])=[CH:24][CH:23]=1
Reactant: NCCc1ccc(OC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 40.7 %

Procedure:
4-[4-(2-Aminoethyl)phenoxy]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.56 g, 1.5 mmol), was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.606 g, 1.5 mmol) according to Procedure G (eluant: 50:1 going to 20:1 dichloromethane-methanol) to give the title compound (0.47 g, 0.61 mmol).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:28][CH2:29][CH3:30])[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:28][CH2:29][CH3:30])[CH2:13]1
Reactant: [H][H]
Reactant: CCCN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Solvent: CCO
Product: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
12 g (ca 30 mM) of 8α-benzyloxycarbonylamino)-6-n-propylergoline obtained from step (d) and 1.5 g palladium on charcoal (10% by weight) in 500 ml ethanol are hydrogenated at normal pressure until hydrogen uptake ceases. The mixture is filtered and concentrated. This resultant heading compound is crystallised from methanol.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].O[C:27]1[CH:31]=[CH:30][O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccon1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
Diisopropyl azodicarboxylate (1.1 ml, 5.5 mmol) was added dropwise to a solution of 2-(t-butoxycarbonylamino)ethanol (850 μl, 5.5 mmol), 3-hydroxyisoxazole (Method 75; 425 mg, 5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with iso-hexane:EtOAc (100:0 increasing in polarity to 4:1) to give the title compound (506 mg, 44%) as a white solid. NMR 1.43 (s, 9H), 3.56 (m, 2H), 4.32 (m, 2H), 4.90 (s, 1H), 5.98 (s, 1H), 8.16 (s, 1H); m/z 229.
Reaction SMILES: [CH:1]1(ON2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:18].NN.Cl>C(O)C>[CH:1]1([CH:4]2[CH:5]=[CH:1][CH:2]=[CH:3][O:18]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: O
Agent: Cl
Agent: NN
Solvent: CCO
Product: C1=COC(C2CCCC2)C=C1
Temperature: 25 °C
Yield: 175.8 %

Procedure:
A mixture of N-cyclopentyloxyphthalimide (11 g), 100% hydrazine hydrate (2.6 g), and ethanol (30 ml) was heated under reflux for 5 minutes. Concentrated hydrochloride acid (6 ml) was added to the mixture, which was heated under reflux Water (20 ml) was added to the mixture, which was cooled to room temperature, and filtered. The filtrate was evaporated to dryness, ethanol (50 ml) was added to the residue, and a small amount of insoluble material was filtered off. The filtrate was evaporated to dryness, and the residue was recrystallised from ethanol/ether to give cyclopentyloxamine (6.28 g,) 96%), m.p. 156.9°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10](C)C)=[C:4]([C:13]#[N:14])[CH:3]=1.N[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[CH3:23].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][N:10]=[C:13]2[NH:14][C:18]1[CH:19]=[C:20]([OH:22])[CH:21]=[CH:16][C:17]=1[CH3:23]
Reactant: Cc1ccc(O)cc1N
Reactant: CN(C)C=Nc1ccc(Br)cc1C#N
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(O)cc1Nc1ncnc2ccc(Br)cc12
Yield: 101.4 %

Procedure:
6.0 g (23.9 mmol) of N′-(4-bromo-2-cyanophenyl)-N,N-dimethylformamidine and 3.24 g (26.3 mmol) of 2-amino-4-hydroxytoluene are suspended in 40 ml of acetic acid and heated under reflux for 1 h. The resulting mixture is cooled and then added to 100 ml of water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. aqueous sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated. 8.0 g (100%) of the desired product are obtained.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH:1]2[CH2:2][CH2:3]2)[CH:9]=1
Reactant: Br[Mg]C1CC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ccnc(C2CC2)c1

Procedure:
The title compound is prepared according to a modification of a procedure described in the literature [Comins, D. L.; Mantlo, N. B., Journal of Organic Chemistry, (1985), 50, 4410-4411]. Cyclopropylmagnesium bromide (0.5M in THF, 100 mL, 50 mmol, 2.2 eq) is added in one portion to a cold (−78° C.) suspension of 4-chloropyridine hydrochloride (3.4 g, 22 mmol) in THF (68 mL).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][P:9]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)[OH:14])(=[O:12])[O:10][CH3:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:7][O:8][P:9]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)[O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:12])[O:10][CH3:11]
Reactant: C1=COCCC1
Reactant: COP(=O)(OC)C(O)c1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C(OC1CCCCO1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
3,4-Dihydro-2H-pyran (10.83 g, 128.70 mmol) and p-toluenesulfonic acid (0.34 g, 1.75 mmol) were added to a solution of [(3-cyanophenyl-hydroxy-methyl]-phosphonic acid dimethyl ester (14.10 g, 58.50 mmol) in dry toluene (195 ml) and the reaction mixture was stirred under nitrogen atmosphere at 50° C. for 3 h. The solvent was then removed under vacuum and the residue was taken up with ethyl acetate (100 ml). The organic layer was washed with a saturated NaHCO3 solution (1×100 ml), brine (1×100 ml) and dried over Na2SO4. The filtrate was evaporated to dryness to give the crude [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic acid dimethyl ester as a yellow oil (19 g, 58.46 mmol, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:25][CH2:24][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[F:22][C:19]([F:20])([F:21])[C@@H:18]([CH3:23])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:4][CH2:3][C:2](=[O:1])[CH2:25][CH2:24]3)[C:9]2=[O:10])=[CH:12][CH:13]=1
Reactant: C[C@@H](Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of 8-hydroxy-2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one (5.79 g) and 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) (506 mg) in CH2Cl2 (85 mL) was added a solution of potassium bromide (482 mg) in water (16 mL). Then, sodiumhypochlorite (13%, 42.5 mL) was added dropwise over a period of 10 minutes followed by sodium bicarbonate (NaHCO3) (4.08 g). The mixture was stirred for 1.5 hours at RT. TLC showed a remainder of starting material. More TEMPO (125 mg) and sodiumhypochlorite solution (10 mL) were added to the reaction mixture and the mixture was stirred for additional 2 hours at RT. The reaction mixture was poured into ice/water and was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The crude material was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to provide the title compound as a light brown solid (5.47 g). MS (m/e): 356.1 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][NH:7][CH2:6]1.[OH-].[NH4+]>C(O)(=O)C>[CH2:22]([O:21][C:19]([C:9]1[C:10]2[NH:11][C:12]3[CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[CH:15]=[CH:16][C:17]=3[C:18]=2[CH2:5][CH2:6][NH:7][CH:8]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.3 %

Procedure:
A solution of nitric acid(90%, 50 uL, 1 mmol) in acetic acid (3 mL) was added dropwise to a stirred solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (256 mg, 1 mmol) in acetic acid (5 mL) at 10° C. The mixture was allowed to warm to ambient temperature and stirred for another 1.5 hours, then poured into a mixture of ammonium hydroxide and ice and extracted with DCM. The combined extracts was washed with brine, dried with sodium sulfate, and evaporated in vacuo. The crude product was purified by chromatography on silica gel eluting with hexane-EtOAc (75:25) to give 8-nitro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (25 mg); 1H-NMR (CDCl3): δ 11.52 (1H, s), 8.78 (1H, d), 8.43 (1H, m), 7.92 (1H, d), 7.82 (1H, dd), 7.46 (1H, d), 4.24 (2H, q), 3.52 (2H, m), 3.07 (2H, m), 1.27 (3H, t); MS (ES): 301 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([Cl:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:15][C:14]=2[CH:24]=1>CN(C)C=O>[Cl:18][C:17]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:24][C:14]=2[S:15][C:16]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Cl
Reaction time: 0.67 h
Yield: 63 %

Procedure:
Imidazole (2.0 g, 30 mmol) was added in portions to a stirred suspension of sodium hydride (0.48 g of 60% dispersion in mineral oil, 12 mmol) in anhydrous dimethylformamide (15 ml) at 0° C., under a nitrogen atmosphere. After 40 minutes, ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 3.33 g, 10 mmol) was added. After 2 hours the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant, and the isolated product was crystallised from diethyl ether to give the title compound as a colourless solid (2.02 g).
Reaction SMILES: [NH3:1].CO[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[NH3:1].[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: CCCCCCCCOC
Agent: N
Product: C=CCCCCCC
Reaction time: 0.5 h

Procedure:
Ammonia gas was slowly bubbled through 1-methoxyoctane (50 mL) for 1 hour to form a saturated ammonia solution in 1-methoxyoctane. Analysis of ammonia in methoxyoctane indicated that the solution was saturated after 30 minutes of bubbling (15 min, 2372 mg NH3/L; 30 min, 3016 mg NH3/L; 60 min, 2924 mg NH3/L; 90 min, 3294 mg NH3/L). The NH3 saturated methoxyoctane solution was used as feed to the cracking reactor. The data are presented in Table 3. (NH3 helps to give higher conversion while maintaining high octene-1 selectivity.)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:29][CH2:30]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(OC(F)F)c21
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21

Procedure:
The same reaction as in Example 1 was carried out by using 1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-(2-pyrimidinyl)piperazine to obtain the title compound as white powder.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:14](O)=[O:15])[CH3:13])=[O:10])[CH3:8])=[O:5])[CH3:3].CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C.O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([CH2:14][OH:15])[CH3:13])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To 5 g (0.014 mol) of Z-Ala-Ala-AlaOH dissolved in THF/DMF 1:1 (50 mL) at −10° C. under a N2 atmosphere were added 1.6 mL (0.014 mol) NMM and 1.9 mL (0.014 mol) IBCF. The reaction mixture was stirred 15 minutes, filtered, and the filtrate added slowly to an ice-cold solution of NaBH4 (1.4 g, 0.037 mol) in H2O (3 mL) and stirred 1 hour at ice-bath temperature and 1 hour at room temperature. The reaction mixture was cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl that is saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude product was purified over a silica gel column eluted with 95:5 EtOAc/MeOH to give 1.2 g product.
Reaction SMILES: [Li]CCCC.CCCCCC.C(#N)C.[CH:15]12[CH2:24]C3CC(CC(C3)[C:16]1=[O:25])[CH2:22]2.[C:26]([CH2:28][C:29]1([OH:39])[CH:36]2[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:38][CH:30]1[CH2:31]3)[CH2:35]2)#[N:27].C(OC(=O)C(C)=C)(=O)C(C)=C.C(N(CC)CC)C>O1CCCC1.CCCCCC.C(OCC)C.O>[C:16]([O:39][C:29]1([CH2:28][C:26]#[N:27])[CH:30]2[CH2:38][CH:34]3[CH2:33][CH:32]([CH2:37][CH:36]1[CH2:35]3)[CH2:31]2)(=[O:25])[C:15]([CH3:24])=[CH2:22]
Reactant: N#CCC1(O)C2CC3CC(C2)CC1C3
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: C=C(C)C(=O)OC(=O)C(=C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(CC#N)C2CC3CC(C2)CC1C3
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A glass reactor of 500 ml which was equipped with a stirrer and dropping funnel was charged with 100 ml of dried tetrahydrofuran, and it was cooled (−78° C.) on a dry ice/isopropanol bath and then charged with 100 ml (160 millimole) of a n-BuLi/n-hexane solution (1.6M). Acetonitrile 10 ml (192 millimole) was dropwise added thereto in 10 minutes. The solution stayed in a slurry state by a deposit. A solution obtained by dissolving 22.2 g (148 millimole) of adamantanone (Adamantanone, manufactured by Idemitsu Petrochemical Co., Ltd.) in 100 ml of tetrahydrofuran was dropwise added thereto. The deposit was slowly dissolved, and the solution became transparent. After finishing dropwise adding, the temperature was slowly elevated up to 0° C., and gas chromatographic analysis was carried out to confirm that adamantanone was completely converted to Li alkoxide of 2-cyanomethyl-2-adamantanol at a selectivity of 99.5%. This reaction liquid was dropwise added in 30 minutes to a solution of 47 ml (318 millimole) of methacrylic anhydride, 45 ml (320 millimole) of dried triethylamine and 100 ml of dried tetrahydrofuran while the solution was cooled to 0° C. on an ice and water bath. After further stirred at 0° C. for 30 minutes, 200 mol of water and 300 ml of diethyl ether were added thereto and stirred. This solution was transferred into a separating funnel of 2 liter to remove an aqueous phase, and then an organic phase was washed with diluted hydrochloric acid to remove a Li salt and a triethylamine salt. Further, this was neutralized by a sodium carbonate aqueous solution and then washed with water. The organic phase was dried on anhydrous magnesium sulfate, and then the solvent was distilled off by means of an evaporator to obtain 38 g of a crude reaction product. n-Hexane 100 ml was added to the crude reaction product, and the solution was cooled while stirring to remove deposited 2-cyanomethyl-2-adamantanol by filtration. Activated carbon was added to the n-hexane solution to confirm that the solution became colorless, and it was filtered off. Then, the solvent was distilled off by means of an evaporator to obtain a colorless liquid. It was analyzed by gas chromatography to confirm that the intended product having a purity of 97.0% was obtained at a yield of 35.0 g. The respective data of 1H-NMR, 13C-NMR and GC-MS are shown below.