Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.Br[CH2:28][C:29]#[N:30]>O>[C:29]([CH2:28][N:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:30]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC#N)c1ccnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl (1-phenyl-1H-pyrazol-5-yl)carbamate (3.80 g), 60% NaH (0.422 g) and THF (60.0 mL) was added bromoacetonitrile (1.93 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.38 g).
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2].Cl.C[OH:26]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[OH:23][C@:3]1([C@:4]2([CH3:5])[C@H:6]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:8]1)[C:1](=[O:26])[CH3:2]
Reactant: CO
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Hg+2]
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
Starting from 3.12 g (0.01 mole) of 17α-ethynyl-17β-hydroxy-androst-4-en-3-one one proceeds as described in Example 9 but after the reaction with mercury(II)-acetate the mixture is not poured onto water but the mixture of 24 ml of concentrated hydrochloric acid and 40 ml of methyl alcohol is added thereto. The reaction mixture is stirred at a temperature of 48° to 50° C. for 8 hours, then it is poured onto water. The separated product is filtered, washed with water and dried. Thus 2.70 g of 17α-hydroxy-pregn-4-ene-3,20-dione are obtained (82.1% of the theoretical yield). The crude product is crystallized from methyl alcohol. Melting point: 212°to 217° C.; [α]D20 =+89° (CHC13, c=1%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]>O.[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Clc1ccc(-c2ccc(N3CCC4(CC3)OCCO4)nn2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCN(c2ccc(-c3ccc(Cl)c(Cl)c3)nn2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
M HCl (10 ml) is added to a mixture of 8-(6-(3,4-dichlorophenyl)pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (500 mg) in water (5 ml). The mixture is stirred for 1 hour at 60° C., cooled to room temperature, diluted with water and neutralized with 4 N NaOH. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give 1-(6-(3,4-dichlorophenyl)pyridazin-3-yl)piperidin-4-one (370 mg). m/z(+) 322/324/326 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]I>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1cccc(Br)n1
Solvent: C1CCOC1
Product: CC(O)c1cccc(Br)n1
Reaction time: 1 h

Procedure:
6-Bromo-2-pyridine carboxaldehyde (1.0 g, 5.37 mmol) in dry THF (20 mL) was cooled to −78° C. followed by adding MeMgI (2.0 mL, 5.91 mmol) dropwise via the addition funnel. The cooling bath was removed. The resulting mixture was stirred for 1 h then quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between water and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4. Solvent was removed and crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (70:30) gave a white solid. MS m/z: 201.9(M+H). Calc'd. for C7H8BrNO-200.98.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]([CH3:24])[CH3:23]>O>[CH3:21][CH:22]([CH3:24])[CH2:23][N:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:13]=[N:12]1
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1cc([N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 276 %

Procedure:
To a DMF solution (30 ml) of 4-nitro-1H-pyrazole (1.00 g) were added potassium carbonate (3.67 g) and 1-bromo-2-methylpropane (1.82 g), and the mixture was stirred at 70° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.13 g, containing DMF).
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:34]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH2:35][CH:36]([CH3:38])[CH3:37]>C(Cl)Cl.CN(C)C=O>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[C:41]([CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH:42]=3)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCn1c(=O)n(CCC(C)C)c2cc(C(=O)O)ccc21
Reactant: CC(C)CCOC(=O)Cc1ccccc1OCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc3c(c2)n(CCC(C)C)c(=O)n3CCC(C)C)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 0.17 g of 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid in 9 ml of methylene chloride are added 60 μl of oxalyl chloride and 20 μl of N,N-dimethylformamide successively. The mixture thus obtained is stirred at ambient temperature for 2 hours. Then, 0.42 g of aluminum chloride and 0.38 g of isopentyl 2-(2-isopentyloxyphenyl)acetate are successively added at ambient temperature, and the mixture thus obtained is stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.29 g of isopentyl 2-[5-[(1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbonyl]-2-(isopentyloxy)phenyl]acetate as a light yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]C)=[O:17])=[CH:7]2.[OH-].[Li+].C(O)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCc1cc2c(c(Cl)c1OC)OC(C(F)(F)F)C(C(=O)OC)=C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc2c(c(Cl)c1OC)OC(C(F)(F)F)C(C(=O)O)=C2

Procedure:
To a solution of 0.14 g(0.4 mmol) of methyl 8-chloro-6-ethyl-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 5 mL of tetrahydrofuran was added a solution of 82 mg (1.95 mmol ) lithium hydroxide in 8 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to reflux for two h. The mixture was concd in vacuo. The residue was diluted with water and acidified to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate and the combinced organic extracts dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 86 mg (64%) of a the product as white solid: 1H NMR (CDCl3/400 MHz) 7.80(s, 1H ), 7.01(s, 1H ), 5.77(q, J=6.8 Hz, 1H), 3.89(s, 3H), 2.62(q, J=7.6 Hz, 2H), 1.21(t, J=7.2 Hz, 3H). MS (ESI+) 337.0 (M+1, 100). MS(ES−) 335.0 (M−H, 100), HRMS (ES−) m/z calcd for (C14H11ClF3O4) M−H: 335.0292, found 335.0297.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[OH-].[NH4+].Cl>O.CO.N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. With stirring, add 28.8 g. of pivalyl chloride (α,α-dimethylpropionylchloride) portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrated ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of 2N-hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Remove the last traces of ethyl acetate in vacuo and crystallize the product from a 9:1 toluene:ethanol mixture to obtain the title product m.p. 143.5°-146° C.
Reaction SMILES: C([NH:18][C@H:19]([C:29]([NH:31][C:32]1[CH:50]=[CH:49][C:35]([O:36][C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41]([NH2:46])=[C:40]3[C:47]#[N:48])=[CH:34][CH:33]=1)=[O:30])[CH2:20][O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(Cl)(Cl)Cl>[C:25]([O:24][C:22]([O:21][CH2:20][C@@H:19]([C:29]([NH:31][C:32]1[CH:50]=[CH:49][C:35]([O:36][C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41]([NH2:46])=[C:40]3[C:47]#[N:48])=[CH:34][CH:33]=1)=[O:30])[NH2:18])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)OC[C@H](N)C(=O)Nc1ccc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of 5-[4-({N-FMOC-O-t-butoxycarbonylseryl}amino)phenoxy]-2-amino-1H-indole-3-carbonitrile (1.45 g; 2.3 mmol) in CHCl3, (30 ml) was treated dropwise with piperidine (3.25 ml). The mixture was stirred for 3 hours at room temperature and was directly purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (2.5 to 10% MeOH). The appropriate fractions were evaporated to give 5-[4-(O-t-butoxycarbonylserylamino)phenoxy]-2-amino-1H-indole-3-carbonitrile as a white solid (878 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]Br>C(O)(=O)C.CN(C)C=O>[Br:15][C:12]1[S:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=Cc1cc(-c2cccnc2F)cs1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
4-(2-Fluoropyridin-3-yl)thiophene-2-carbaldehyde (3.35 g) was dissolved in acetic acid (20 mL) and N,N-dimethylformamide (20 mL), and bromine (7.77 g) was added at room temperature. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residue was weakly basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=6:1→3:1), and the obtained solid was washed with diisopropyl ether to give the title compound as a pale-yellow powder (yield 1.79 g, 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:10]1[C:6]2[CH2:7][CH2:8][O:9][C:5]=2[C:4]([NH2:11])=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N)c2c(c1)CCO2
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1Br)CCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-methyl-2,3-dihydrobenzofuran-7-amine (1d) (1.0 g, 6.7 mmol) in DMF (21 mL) at 0° C., was added NBS (1.19 g, 6.7 mmol), it was stirred at 0° C., for 15 min. The mixture was extracted with EtOAc (150 mL), washed with saturated NaHSO3 (50 mL), water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (1e) as a yellow solid. MS-ESI (m/z): 228 (M+1)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[O:18]=[C:19]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N=C(Nc1ccccc1)c1cccnc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Temperature: 160 °C

Procedure:
A suspension of the N-phenyl-3-pyridinecarboximidamide (i.e. the product from Example 7, Step A) (36.5 g, 185 mmol) in diethyl ethoxymethylenemalonate (60 g, 280 mmol) was heated to 160° C. for 8 h. Ethanol formed in the reaction was collected using a distillation head attached to the flask containing the heated reaction mixture. The reaction mixture was then cooled to ambient temperature when the formation of a solid was observed. A mixture of diethyl ether/petroleum ether (8:2) was added to the reaction mixture was filtered. The collected solid was washed with additional ether/petroleum ether (4:1) followed by n-chlorobutane/petroleum ether (1:1) to obtain 51 g of the title compound as a light brown powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reaction time: 8 h

Procedure:
To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridine (20. g, 130 mmol, Adesis) in DCM (200 mL) was added benzenesulfonyl chloride (20. mL, 160 mmol, Aldrich), triethylamine (27 mL, 200 mmol) and 4-dimethylaminopyridine (0.80 g, 6.6 mmol, Aldrich). The reaction mixture was stirred overnight. Water was added and the mixture was stirred for 4 h. Layers were separated and the organic phase was washed sequentially with 1 N HCl, water, saturated solution of NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give an orange solid, which was triturated with MeOH (100 mL). The solid was filtered, washed with MeOH, and dried at 40° C. under high vacuum overnight. Additional product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-60% EtOAc in hexanes). Yield: (26.8 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([SH:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:14][CH2:12][CH3:13]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C
Yield: 96.4 %

Procedure:
To 3-bromo-4-fluoronitrobenzene (7.05 g, 32.0 mmol) and ethanethiol (2.6 mL, 35.2 mmol) in DMF (20 mL) was added potassium carbonate (4.87 g, 35.2 mmol). The reaction mixture was heated to 60° C. overnight. After cooling, the mixture was filtered over celite and washed with ethyl acetate. The combined filtrate and washings were concentrated. The residue was redissolved in ethyl acetate and washed with water (3×) and then dried over sodium sulfate. The filtrate was concentrated and purified by flash column chromatography to give 100A (8.09 g, 96% yield) as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.41 (t, J=7.34 Hz, 3H) 3.11 (q, J=7.42 Hz, 2H) 7.45 (d, J=9.05 Hz, 8H) 8.17 (dd, J=8.80, 2.45 Hz, 7H) 8.37 (d, J=2.45 Hz, 7H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[O:20]([CH2:19][C:11]1([CH2:10][CH2:9][OH:8])[CH2:12][O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16]1)[Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)OCC(CCOCc2ccccc2)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CCO)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.3 %

Procedure:
570 mg (1.56 mmol equivalents) of 5-benzyloxyethyl-2,2-dimethyl-5-(t-butyldiphenylsiloxymethyl)-1,3-dioxane was dissolved in 30 mL of ethyl acetate, 100 mg of palladium carbon was added thereto under argon atmosphere, and the mixture was stirred under hydrogen atmosphere at room temperature (25° C.) for 22 hours. After completion of the reaction, a precipitate was filtered, and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 174 mg (0.41 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-hydroxyethyl-1,3-dioxane.
Reaction SMILES: [OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[C:16]([C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([CH2:30][CH2:31][C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[C:37](=[O:49])[CH:38]([CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[C:39]([O:41]CC)=[O:40])[N:25]2[CH2:28][CH3:29])=[CH:21][CH:20]=1)(=[NH:18])[NH2:17]>C(O)C>[C:16]([C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([CH2:30][CH2:31][C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[C:37](=[O:49])[CH:38]([CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[C:39]([OH:41])=[O:40])[N:25]2[CH2:28][CH3:29])=[CH:21][CH:20]=1)(=[NH:17])[NH2:18]
Reactant: CCOC(=O)C(C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC)C1CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(CC[C@@H]2CCCN2C(=O)C(C(=O)O)C2CCCC2)cc2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 67.8 %

Procedure:
In a 50 ml flask, 80 mg of ethyl 3-[(S)-2-[2-(6-amidino-1-ethylindol-2 -yl)ethyl]pyrrolidinyl]-2-cyclopentyl-3-oxopropanoate obtained in Example 33 was dissolved in 20 ml of ethanol, and 10 ml of 2N NaOH was added thereto. The reaction mixture was stirred for 10 hours at room temperature, neutralized with 10% aqueous citric acid solution, and then distilled under reduced pressure to remove the solvent. The residue was then purified with column chromatography [eluent: ethyl acetate/methanol (5:1)] on NH-DM1020 silica to obtain 51 mg of the title compound as a yellowish white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:51]>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]>[ClH:27].[ClH:51].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Temperature: 80 °C

Procedure:
To a suspension of 1-(6-bromo-4-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.22 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with a satd. aq. NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with a mixture of CHCl3/isopropanol (3:1). The desired fractions were concentrated and dissolved in methanol and resultant residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol) was added. The resulting solution was concentrated to give the desired product (55.9 mg, 67%) as an off-white solid NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.50 (s, 1H), 8.27 (dd, J=8.7, 1.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J=11.4, 2.3 Hz, 1H), 4.54-4.50 (m, 1H), 3.25-3.17 (m, 2H), 2.90 (s, 6H), 2.73 (s, 3H), 2.42 (d, J=12.2 Hz, 2H), 2.04 (d, J=12.9 Hz, 2H), 1.80-1.68 (m, 4H), 1.59 (br s, 1H), 1.39-1.27 (m, 2H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC>99% (AUC), tR=10.01 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1
Reactant: NCC1CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCC2CC2)ncn1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
In a microwave reaction vessel, slurry 4,6-dichloropyrimidine (540 mg, 3.6 mmol), cyclopropylmethylamine (2800 L, 3.24 mmol), and diisopropylethylamine (1.25 mL, 7.2 mmol) in iso-propanol (3 mL). Irradiate in microwave (300 watts) at 140° C. for 40 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 3:1 over 30 min; 40 mL/min) to obtain the desired intermediate (567 mg, 86%) as an off-white solid. MS (ES+) m/z: 184 (M+H)+.