Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.COCCOC.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:48])([F:47])[F:46])[OH:44])=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]([C:28]2[CH:29]=[CH:30][C:31]([C:2]3[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:32][CH:33]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:46])([F:47])[F:48])[OH:44])=[N:24]1
Reactant: CC1(C)OB(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)OC1(C)C
Reactant: Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ncccc1-c1ccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccc(F)cc2F)cc1
Temperature: 88 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To 3-bromo-2-methylpyridine (25.0 mg, 0.14 mmol), were added 1,2-dimethoxyethane (1.5 mL) and Pd(PPh3)4 (8.5 mg, cat.). To the reaction mixture, were added 1-(2,4-difluoro-phenyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (40.0 mg, 0.07 mmol) prepared in Step 1, ethanol 364.0 uL, and a 2N sodium carbonate solution (364.0 uL). The reaction mixture was stirred at 88° C. for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 3.3 mg of the titled compound as a yellow liquid.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH3:6].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH2:40])[NH:38][N:39]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH:40][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([CH:10]4[CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[CH2:12][CH2:11]4)=[CH:22][CH:21]=3)[NH:38][N:39]=2)[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Temperature: 60 °C
Yield: 38 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.413 mL, 0.83 mmol), was added drop-wise to a suspension of methyl 4-(1-ethylpiperidin-4-yl)benzoate (0.082 g, 0.33 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.082 g, 0.33 mmol) in toluene (2 mL) at room temperature. The solution was then heated at 60° C. for 18 h. The reaction mixture was cooled, quenched with methanol (2 ml) and 2N hydrochloric acid (1 ml). The reaction mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.058 g, 38.0%) as a white solid.
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[O-:19][CH2:20][CH3:21].[Na+].C(O)C.C[O-].[Na+].CO>>[CH2:20]([O:19][C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)[CH3:21]
Reactant: CC[O-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 34, 3-methylsulfonyl-11H-s-triazolo[3,4-b][3] benzazepine was reacted with sodium ethoxide/ethanol, in lieu of sodium methoxide/methanol, to obtain 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from acetone yielded colorless needles, melting point: 143°-144° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH2:33][C:34]2[O:38][C:37]([C:39](OC)=[O:40])=[N:36][N:35]=2)[CH3:32])(=[O:30])=[O:29])=[C:23]([CH3:43])[CH:22]=1.CO>C1COCC1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH3:32])[CH2:33][C:34]2[O:38][C:37]([C:39]([N:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH2:14][CH2:13]3)=[O:40])=[N:36][N:35]=2)(=[O:30])=[O:29])=[C:23]([CH3:43])[CH:22]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)o2)c(C)c1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
1-(3-Pyrrolidin-1-ylpropyl)piperazine (128 mg, 1.65 mmol) was dissolved in THF (5 mL) and the resulting solution was cooled to −40° C. prior to the addition of trimethylaluminium (2 M in toluene, 0.59 mL). The reaction was stirred for 15 min at −40° C. and a solution of methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (200 mg, 0.54 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at ambient temperature for 18 h and MeOH (5 mL) was added. The solvents were removed in vacuo and the resulting residue was purified by FCC, eluting with 0-2% MeOH in DCM to afford the title compound as a pale yellow semi solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1C(=O)N([Cl:17])C(=O)C1>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cccc(N)c1
Product: CCc1cc(N)ccc1Cl

Procedure:
Prepared from 7.36 g of 3-ethyl-phenylamine and 8.12 g NCS. Yield: 4.4 g. LC-MSD, m/z for C8H10ClN [M+H]+=156.0, 158.0;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorothiophenol (5.04 g, 28.2 mmol), caesium carbonate (10.1 g, 31 mmol) and ethyl 3-bromopropanoate (4.2 mL, 33 mmol) in acetone (100 mL) were refluxed overnight under N2(g). After filtration and concentration under reduced pressure, the residue was partitioned between dichloromethane and water. After separation, the aqueous phase was extracted once with dichloromethane. Drying and removal of the solvent in vacuo afforded a liquid residue that contained ˜30% (HPLC) of unreacted 2,4-dichlorothiophenol. The mixture was refluxed again with caesium carbonate (4.7 g) and ethyl 3-bromopropanoate (2 mL) in acetonitrile (100 mL) under N2(g) for 2 h. After filtration and concentration under reduced pressure, the residue was dissolved in diethyl ether and washed with 2 M aq. sodium hydroxide and water. Drying and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.8 %

Procedure:
To 100 ml of conc. sulfuric acid was dissolved 31 g of 2,4,5-trifluoro-3-methylbenzoic acid, and to this solution was incrementally added 19.5 g of potassium nitrate on ice. The solution was stirred at room temperature for 3 days, and another 1.4 g of potassium nitrate was added on ice. After stirring for 6 hours, the solution was poured into ice water, and the solid precipitate was collected by filtration. The precipitate was dissolved in diethylether and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid precipitate was collected by filtration to obtain 21 g of the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:12][CH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[N:3]=[C:2]2[I:1])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cn1nc(I)c2cc(CO)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cn1nc(I)c2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of (3-iodo-1-methyl-1H-indazol-5-yl)-methanol (810 mg, 2.81 mmol) in DMF (9 mL) was added imidazole (479 mg, 7.03 mmol) followed by tert-butyldimethylsilyl chloride (466 mg, 3.09 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% EtOAc/hexanes to afford 732 mg (65%) of 5-(tert-butyldimethylsilanyloxymethyl)-3-iodo-1-methyl-1H-indazole as a pale yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.26-7.34 (m, 2H), 7.17-7.23 (m, 1H), 4.73 (s, 2H), 3.97 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][N:28]=4)[CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][N:28]=4)[CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc3c(c2)CCC(OC)C3)cc1)c1nncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCc2cc(COc3ccc([C@H](CC(=O)O)c4nncn4C)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 45.4 in THF/MeOH (1:1, 2 mL), is treated with 2N NaOH aqueous solution (1 mL) and stirred for overnight at room temperature. The reaction mixture is acidified with aqueous 2N HCl and extracted with EtOAc to obtain 45, which is purified by preparative HPLC, eluting with 5-95% ACN in water containing 0.1% TFA.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2cccc(F)c2)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=318 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]([CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])=[O:23]>>[CH:1]1([CH2:7][N:8]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]([O:21][CH3:20])=[O:23])[CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(CCNCC3CCCCC3)c[nH]c2c1
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC1CCCCC1
Yield: 84.5 %

Procedure:
12.0 g of N-cyclohexylmethyl-tryptamine and 8.47 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 15.2 g of N-cyclohexylmethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-cyclohexylmethyl-4-methoxycarbonylbutanamido)-ethyl]-indole) were thereby obtained. Yield: 84.9%
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[I:14]I.Cl>C1(C)C=CC=CC=1>[I:14][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9]
Reactant: II
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1cc(C(F)(F)F)ccc1I
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
A toluene (200.0 mL) solution of 3-trifluoromethylphenol (16.6 g) was added dropwise to a toluene (300.0 mL) suspension of sodium hydride (7.1 g) under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes, and iodine (26.0 g) was then added thereto. The solution was stirred at room temperature for 12 hours. Subsequently, 3 N hydrochloric acid was added to the solution so that the pH of the solution was adjusted to 2. The solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (30.8 g) was obtained as pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:12][C:10]([CH:9]=[CH:3][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:11])[CH3:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(C=O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (6.1 g, 0.15 mol) was dissolved in tetrahydrofuran. Subsequently, triethylphosphonoacetate (30.2 mL, 0.15 mol) was added dropwise under ice-cooling. After 30 minutes, tert-butyl 2-(3-formylphenoxy)-2-methylpropionate (33.6 g, 0.13 mol) was added under ice-cooling, the mixture was stirred for one hour. Thereafter, the temperature of the mixture was raised to room temperature, and the mixture was stirred for five hours. An aqueous ammonium chloride solution was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=9/1), whereby the target compound was obtained (39.1 g, 92%).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:12][CH:11]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.Cl>CO.O1CCOCC1>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:10][CH:11]([NH:13][C@H:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)[CH2:12]2)=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC2CN(C(=O)c3ccc(-c4ccccc4)cc3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CC(N[C@H]2CCNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 3e (2.5 g, 5.92 mmol) in MeOH (7 mL) was added an HCl solution in dioxane (4M, 12 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (30 mL) was added to the residue. The off-white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 3f was used in the next reaction without further purification. MS m/z (M+H+) 322.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])[CH2:30]2>>[Br:24][C:25]1[CH:26]=[C:27]([F:35])[CH:28]=[C:29]2[C:33]=1[NH:32][C:31](=[O:34])/[C:30]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 40 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 12b as starting materials to give (R,Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 14 (20 mg, yield 40%) as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][C:34]([C:40](=[NH:42])[NH2:41])=[CH:35][CH:36]=4)[CH:31]=3)[S:20]([CH2:23][C:24]([O:26]CC)=[O:25])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[NH:5])[CH3:4]>Cl>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:14]=[CH:15][C:16]([N:19]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][C:34]([C:40](=[NH:41])[NH2:42])=[CH:35][CH:36]=4)[CH:31]=3)[S:20]([CH2:23][C:24]([OH:26])=[O:25])(=[O:22])=[O:21])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)(=[NH:5])[CH3:4]
Reactant: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCN(C(C)=N)CC2)cc1
Agent: Cl
Product: CC(=N)N1CCCN(c2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)S(=O)(=O)CC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 140.4 %

Procedure:
450 mg of ethyl [N-[4-(4-acetimidoylhexahydro-1 H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)-methyl]sulfamoyl]acetate dihydrochloride obtained in Example 22 was dissolved in 8 ml of concentrated hydrochloric acid, and stirred at room temperature for 14 hours. The reaction mixture was evaporated, and the resulting residue was dissolved in 8 ml of concentrated hydrochloric acid, and stirred at room temperature for 4 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography using an eluent solvent of acetonitrile/water (10/90). A small amount of 1 N hydrochloric acid was added to this, which was then freeze-dried to obtain 302 mg of [N-[4-(4-acet-imidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetic acid dihydro-chloride.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=[CH:19][CH:20]=1.O>CN1C(=O)CCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[NH2:21])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (4 g, 21.5 mmol) and 3-fluoronitrobenzene (2.3 ml, 21.5 mmol) in anhydrous NMP (5 ml) was heated to 120° C. for 3 days. After cooling water (25 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography using successively petroleum ether and a mixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluents. Yield of t-butyl 4-(3-nitrophenyl)-1-piperazinecarboxylate: 1.34 g (20%). This intermediate was quantitatively hydrogenated to 2g in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:30]=1[CH2:31][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[C:29]([F:28])=[CH:36][CH:35]=[CH:34][C:33]=5[F:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5c(F)cccc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.91 min; Mass spectrum (ESI+): m/z=491 [M+Na]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=2)[CH2:19]1)[C:10](=O)[CH2:11][CH2:12][C:13](OC)=[O:14])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:9]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=2)[CH2:19]1)[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:8]
Reactant: CCN(C(=O)CCC(=O)OC)C1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCCCO)C1CCc2cc(OC)ccc2C1
Yield: 85.8 %

Procedure:
To a suspension of 8.3 g of lithium aluminum hydride and 200 ml of anhydrous tetrahydrofuran, a solution of 14.5 g of N-ethyl-N-[3-(methoxycarbonyl)propionyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise. After heating the resulting solution for 4.5 hours at reflux, a mixed solution of 8.3 ml of water and 50 ml of tetrahydrofuran as added dropwise to the solution under cooling with ice. Then, 8.3 ml of a 15% sodium hydroxide aqueous solution was added dropwise to the resulting solution and lastly 25 ml of water was added dropwise thereto to precipitate insoluble materials. After removing the insoluble materials by filtration, the filtrate was concentrated under reduced pressure to obtain a residue. After the residue was extracted with benzene, the benzene layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 10.8 g of N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a colorless oily product. This product was treated with an ethanolic solution of hydrogen chloride having a concentration of about 18% to obtain N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride as colorless crystals having a melting point of 124°-126° C.