Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)O)oc1Cl
Yield: 47.2 %

Procedure:
A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.25 mmol) in 6N sodium hydroxide (4.16 ml, 24.93 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (267 mg, 0.59 mmol, 47% yield) as a white foam: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Mg].I[CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 4-isopropyloxy benzaldehyde of formula 5 (5 g, 30 mmol) in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodomethane (2.6 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is worked up by adding saturated aqueous solution of ammonium chloride (10 ml), followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer is washed with water (2×20 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-(4-isopropyloxy phenyl) ethanol, in a semisolid of general formula 4 in 92.5% yield.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(N)=O
Reactant: CN1CCNCC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Yield: 95 %

Procedure:
1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95%) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam.
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2O)[CH:8]=[CH:7]1.C(Cl)(=O)C([Cl:19])=O>ClCCCl>[Cl:19][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[CH:7][S:6][C:14]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ccnc2ccsc12
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2ccsc12
Reaction time: 2 h

Procedure:
To a stirred solution of POCl3 (28.6 mL, 313 mmol) in 1,2-dichloroethane (200 mL) was added commercially available thieno[3,2-b]pyridin-7-ol (94.7 g, 626 mmol) as a powder in one portion. The reaction was stirred for 2 hours at reflux under N2. The mixture was concentrated, using toluene (3×100 mL) to azeotrope. The dark residue was resuspended in CH2Cl2 (1 L), and a saturated aqueous solution of NaHCO3 (500 mL) was carefully added. The mixture was stirred for 30 minutes until bubbling had ceased. The biphase was separated, and the aqueous was re-extracted with CH2Cl2 (500 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated, to obtain a brown oil, which crystallized upon standing (38.4 g, 71%). 7-Chlorothieno[3,2-b]pyridine has also been prepared using oxalyl chloride (WO 99/24440). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=5 Hz, 1H), 7.80 (d, J=6 Hz, 1H), 7.60 (d, J=6 Hz, 1H), 7.29 (d, J=5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccn2c(-c3ccnc(Cl)c3)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1

Procedure:
7-Chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1 eq, 1.136 mmol, 300 mg) and phenyl boronic acid (1 eq, 1.136 mmol, 138 mg) are dissolved in DME (3 ml) and water (1 ml) and Na2CO3 (2 eq, 2.27 mmol, 282 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.114 mmol, 79.7 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=306
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of iodobenzene (1 mmole) in DMF (5 mL) was treated with trimethylsilylacetylene (2 mmole), Pd(PPh3)2Cl2 (0.035 mmole), CuI (0.08 mmole) and triethylamine (4 mmole), and the resulting reaction mixture was stirred under nitrogen at room temperature for 5 h. Evaporation followed by chromatography gave 1-trimethylsilyl-2-phenylacetylene as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:28]=[O:29].O>C(OCC)C>[CH3:13][C:10]1([CH3:14])[O:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[N:3][CH:4]=2)[CH2:12][O:11]1
Reactant: CC1(C)OCC(c2ccc(Br)nc2)O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(c2ccc(C=O)nc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a solution of 2-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (4.12 g) in diethyl ether (100 mL) was slowly added a 1.6M n-butyllithium hexane solution (10 mL) at −78° C. The reaction mixture was stirred for 30 min, and N,N-dimethylformamide (1.40 g) was added. The reaction mixture was warmed to room temperature over 1 hr, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (900 mg, yield 27%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 208 (MH+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]([F:16])[C:12]([O:14]C)=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1>CO>[F:3][C:4]1[CH:5]=[C:6]([CH:11]([F:16])[C:12]([OH:14])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)C(F)c1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
15 ml of a sodium hydroxide solution (1N) are added to 1.9 g of methyl (3,5-difluorophenyl)-fluoroacetate, obtained in step 2.2, in 60 ml of methanol and the mixture is stirred for 18 hours at room temperature. The medium is concentrated under vacuum, the residue is taken up in ethyl acetate and washed with an aqueous hydrochloric acid solution (0.5 M). The organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.6 g of an orange-colored oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)C(COCc1ccccc1)CC(CO)NC(=O)OC(C)(C)C
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(COCc1ccccc1)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 22 h

Procedure:
A solution of 14.70 g of tert-butyl (3-benzyloxymethyl-1-hydroxymethyl-4-methylpentyl)carbamate and 0.24 g of p-toluenesulphonic acid monohydrate in 82 ml of dichloromethane at 0° C. is admixed with 8.2 ml of 2-methoxypropene. After 22 hours at room temperature, the mixture is poured onto 1M aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×)—the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.30 (gradient I).
Reaction SMILES: [CH:1]1([C:13]([OH:15])=[O:14])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH:2]1[C:10]([OH:12])=O>O>[CH:1]12[C:13](=[O:14])[O:15][C:10](=[O:12])[CH:2]1[CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2
Reactant: O=C(O)C1CCC(C(=O)O)C(C(=O)O)C1
Solvent: O
Product: O=C(O)C1CCC2C(=O)OC(=O)C2C1
Temperature: 250 °C

Procedure:
Into a four-necked flask equipped with a thermometer, a stirrer, a condenser and a temperature controller, 100 parts by mass of cyclohexane-1,2,4-tricarboxylic acid was placed and melted by heating at 250° C. for 3 hours while formed water was removed to the outside of the system with a stream of nitrogen gas, and 1,2,4-cyclohexanetricarboxylic acid 1,2-anhydride was obtained. as a light yellow transparent liquid substance The yield of the anhydride was 95% based on the amount of cyclohexane-1,2,4-tricarboxylic acid used as the raw material. The obtained liquid 1,2,4-cyclohexanetricarboxylic acid had a viscosity of 14.6 Pa·s at 60° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(CC)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc(O)cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1-c1ccccc1

Procedure:
Twenty-six grams (92.4 m mole) of 5-hydroxy-3-phenyl-1H-2-indole carboxylic acid ethylester were refluxed for four days with 27.6 g of potassium carbonate and 11 ml (92.4 mole) of benzylbromide in 700 ml of methyl-ethylketone. After filtration and evaporation, the residue was chromatographed on silicagel (solvent: toluene).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](O)(=[O:16])[CH3:15]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>[C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C(C)C)cccc1C(C)C

Procedure:
A suspension of 2,6-diisopropylphenol (5.32 g) in 35 ml of trifluoroacetic anhydride is treated with 1.75 ml of glacial acetic acid under a nitrogen atmosphere. Upon completion of the addition of acetic acid, the solids are in mixture. Solvent evaporation gives an oil which is taken up in 150 ml of ethyl acetate and washed twice with saturated aqueous sodium bicarbonate and once with saline. Drying of the organic layer with sodium sulfate followed by filtration and solvent evaporation gives 6.55 g of an oil which is chromatographed on 330 g of silica gel eluting with chloroform/hexane (9/1). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, TMS) 7.2, 2.91, 2.36, 1.20.
Reaction SMILES: Cl.[C:2]([Cl:10])(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:39][CH2:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:36][CH2:35]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]>>[ClH:10].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:35][CH2:36][N:37]([C:2]([C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[O:9])[CH2:38][CH2:39]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)c4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from isonicotinoyl chloride hydrochloride and starting compound A2 as described for compound 1. After evaporating the dichloromethane solution, the residue is dissolved in diethyl ether. After addition of a saturated solution of hydrochloric acid in ether, the titel compound precipitates. M. p. 66-68° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:30]1([S:40](Cl)(=[O:42])=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[C:30]1([S:40]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=5)=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:6]=3)[CH2:1]2)(=[O:42])=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=C(Nc1ccc2c(c1)CCN(S(=O)(=O)c1cccc3ccccc13)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydroisoquinolin6-yl]-amide was prepared by METHOD D reacting compound II with naphthalene-1-sulfonyl chloride.
Reaction SMILES: Cl.[CH2:2]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[OH:10])[CH2:3]1.CCN(CC)CC.CC(O)=O.C(OC([N:29]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH2:38][CH:39]=O)[CH2:31][CH2:30]1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][C@@H:5]1[CH2:6][N:7]([CH2:39][CH2:38][CH2:37][N:32]2[C:33](=[O:36])[CH2:34][CH2:35][NH:29][CH2:30][CH2:31]2)[CH2:8][CH2:9][C:4]21[CH2:3][CH2:2]2
Reactant: O[C@@H]1CNCCC12CC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCNCCN1CCCN1CCC2(CC2)[C@H](O)C1
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) 0.16 g (1 mmol) in CH2Cl2 (5 ml) was added Et3N 0.14 ml (1 mmol) and AcOH 0.11 ml (2 mmol) followed by a solution of 5-oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester 0.34 g (1 mmol) in CH2Cl2 (5 ml) and finally sodium triacetoxyborohydride 0.25 g (1 mmol). The mixture was stirred for 1 h after which time sat. aq. NaHCO3. solution was added, the reaction extracted with in CH2Cl2, dried (Na2SO4) and concentrated. The residue was taken up in 1 M HCl solution in dioxane (10 ml), stirred for 10 minutes before the solvent was evaporated. The residue was then dissolved in sat. aq. NaHCO3. solution the water removed by evaporation, and the solid extracted with CH2Cl2:MeOH (9:1). Concentration afforded the title compound 0.2 g (71%) as yellow oil. MS: 282.1 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]#[N:44])[CH:41]=3)[NH:36][CH:35]=2)(=O)=O)=CC=1.C(N(CC)CC)C.CN(C)C=O>O>[C:43]([C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5]1)#[N:44]
Reactant: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2c[nH]c3ccc(C#N)cc23)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(N3CCN(CCCCc4c[nH]c5ccc(C#N)cc45)CC3)ccc2o1
Temperature: 79.5 °C
Reaction time: 0.75 h
Yield: 121.7 %

Procedure:
Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (5 g), 3-[4-(p-toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile (6.3 g) and triethylamine (7 ml) were added to dimethylformamide (6.3 ml) and the resulting mixture was heated to 77-82° C., followed by stirring for 45 minutes at the same temperature. Water (30 ml) was added to the reaction mass and then stirred for 5 minutes at 25-30° C. The separated aqueous layer was extracted two times with toluene (2×250 ml). The resulting organic layers were combined and then washed two times with water (2×250 ml) and then distilled off the solvent under vacuum to produce 9.5 g of the titled compound as a residue. Methanol (47.5 ml) was added to the residue at 25-30° C. and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with chilled methanol (10 ml) and then dried the material at 70-75° C. to produce 6 g of Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate (Purity by HPLC: 99%; Yield: 76.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:48][CH2:49][C:50]1[S:54][C:53]([C:55](=[N:57]O)[NH2:56])=[C:52]([CH2:59][CH3:60])[CH:51]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:59]([C:52]1[CH:51]=[C:50]([CH2:49][OH:48])[S:54][C:53]=1[C:55]1[N:57]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[C:2]([F:1])[CH:3]=2)[O:7][N:56]=1)[CH3:60]
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-fluoro-4-(3-fluorophenoxy)benzoic acid (0.13 g, 0.53 mmol) that was obtained in Example 20 (20a), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), and 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.0 mL, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.18 g) in a yield of 87% as a pale yellow crystalline solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C([O-])(=O)C.[Na+].O>ClCCl.C(OCC)(=O)C>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3ccc(C(F)(F)F)cc3)cnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4ccc(C(F)(F)F)cc4)nc23)C2CC2)C1
Yield: 69.8 %

Procedure:
2-(4-Trifluoromethylphenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (62 mg, 0.104 mmol) was dissolved in 0.8 mL of dichloromethane and then stirred in an ice bath. Trifluoroacetic acid (0.4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 2.5 h and then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (170 mg, 2.07 mmol) was added and the mixture was stirred at 60° C. for overnight. The reaction was cooled, and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 34 mg (70%) of 2-(4-trifluoromethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=469; mp=207-209° C.