Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[F-].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29]>C(#N)C>[CH2:26]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Reactant: CCCCBr
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)c2nn(CCC)c3ccccc23)CC1
Yield: 69 %

Procedure:
To a suspension of N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.52 g) obtained in Example 20 in acetonitrile were successively added 50% potassium fluoride--Celite (1.10 g) and 1-bromobutane (0.22 ml), and the mixture was heated under reflux for 11 hours. The reaction solution was filtered off, distilled off under reduced pressure, and to the residue was added chloroform and saturated aqueous sodium hydrogencarbonate. After extraction with chloroform, the chloroform layer was dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (0.42 g) as a yellow oily substance. Yield=69%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.C([O:18]N=O)CC(C)C.Cl.O>C(O)C.C(Cl)(Cl)Cl>[OH:18][C:7]1[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]=1[CH3:1]
Reactant: CC1CC(=O)c2ccccc2O1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1oc2ccccc2c(=O)c1O
Reaction time: 2 h
Yield: 51 %

Procedure:
2,3-dihydro-2-methyl-4H-1-benzopyran-4-one (1.62 g) is dissolved in ethanol 95% (50 ml) and the solution is refluxed under stirring. In 10-15 minutes isoamylnitrite (8 ml) and concentrated HCl (40 ml) are added drop by drop. Heating and stirring are stopped, and the resulting mixture is allowed to stand ca. 2 hours. Then water (200 ml) is added until precipitation of a white solid. The solvent is evaporated, obtaining a solid product which is dissolved in a little volume of chloroform and purified on silica gel in equilibrium with the same solvent. The purified product contains a low percentage of yellow impurities which can be completely eliminated by crystallisation in acetone. The residual solvent is then eliminated, obtaining 0.97 g of 3-hydroxy-2-methyl-4H-1-benzopyran-4-one (colourless crystals; m.p.=179-180° C.; IR: 1632, 1666 e 3301 cm−1; yield=51%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7](OC(OCC)OCC)C.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20]>CCCCCC>[NH:3]1[C:2]([NH:1][CH:7]=[N:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([O:26][CH3:27])=[O:25])=[N:6][N:5]=[N:4]1
Reactant: COC(=O)c1ccccc1N
Reactant: Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of 5 g of 5-aminotetrazole, 46.7 g of triethoxymethane, 10.5 g of methyl anthranilate and 105 ml of hexane was heated at reflux under nitrogen for 48 hours. The mixture was cooled to room temperature and the white crystalline product was separated by filtration, washed with hexane and vacuum oven dried to give product containing traces of methyl anthranilate. This was triturated with additional hexane, followed by filtration and drying to give pure N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=1)=[O:20].C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1C(=O)C1C=CC(OCCCN(CCCC)CCCC)=CC=1)CCC.[H][H]>[Pt]=O>[CH2:4]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH2:14])=[CH:8][C:7]=2[C:6]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)[CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: O=[Pt]
Agent: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1

Procedure:
A process for the preparation of dronedarone was reported in the above said patent EP 0 471 609, according to which process 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-nitrobenzofuran is reduced under pressure with hydrogen in the presence of platinum oxide as catalyst to form 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran (hereinafter Compound A), which is subsequently treated with methanesulfonyl chloride, in the presence of an acid acceptor, to give the desired compound. According to this process, dronedarone could be obtained with an overall yield of the order of 60%, starting from the 5-nitrobenzofuran derivative.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=NNC=2)O1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[CH3:34][C:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[C:38]([CH3:49])[NH:37][N:36]=1>>[CH3:34][C:35]1[C:39]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[C:38]([CH3:49])[NH:37][N:36]=1
Reactant: Clc1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1n[nH]c(C)c1-c1ccc(C2(c3ccccc3)CCNCC2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 4-(4-chloro-phenyl)-4-phenyl-piperidine and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, the title compound was obtained. LC/MS: (PS-A2) Rt 2.95 [M+H]+ 315. 1H NMR (Me-d3-OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m), 3.16-3.28 (4H, m), 7.19-7.44 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([F:9])[CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=2[F:19])[OH:16])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: O=Cc1ccc(Cl)cc1F
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(Cl)cc1F)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (23.87 mmol) of 4-chloro-2-fluorobromobenzene and 4.54 g (28.65 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. A difference was that a preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) was carried out before the purification of the crude product by preparative HPLC. 1.79 g (26% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5g, 0.127 moles) and 1-iodohexane (3.75 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours. The mixture is diluted with ether (300 mL) and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil. (Mass spectrometry also revealed a small amount of diethyl 1,3-dihexyl-2,5-dioxo-4-imidazolylphosphonate) MS (EI) 321
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12]O)[CH2:7][CH2:6][CH2:5]2.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28]N[CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([N:12]1[CH2:28][CH2:29][C:24]3([N:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21][NH:22][C:23]3=[O:30])[CH2:25][CH2:26]1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ON=C1CCCc2cc(Cl)ccc21
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3cc(Cl)ccc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=396.2 (M+H+) was prepared in accordance with the general method of example 11 from 6-chloro-3,4-dihydro-1(2H)-naphthalenone oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 70 %

Procedure:
As described for example 12, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using isopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (trituration with tert-butylmethylether, 158 mg, 70%) which was obtained as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.Cl[C:21]([O:23][CH3:24])=[O:22].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:21]([O:23][CH3:24])=[O:22])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 83.7 %

Procedure:
In 20 ml of pyridine was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.5 g of methyl chloroformate was added to the solution with stirring with cooling at 5° to 10° C. over a period of 20 minutes. After stirring was effected at the same temperature for 2 hours and then at room temperature for 1 hour, the reaction solution was treated with water, and extracted with dichloromethane, followed by washing with dilute hydrochloric acid and water, successively, and drying over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure, and the residual, oily substance was purified by means of column chromatography with the use of silica gel (developing solvent of acetone-hexane), thereby producing 3.0 g (yield of 84%) of the subject compound in white crystals, m.p. 80°-81° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[CH2:15][C:16]([CH2:18]Cl)=O.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]3[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]3)=[CH:31][CH:30]=2)[C:24]([C:44]#[N:45])=[C:23]([SH:46])[N:22]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:20][C:21]1[N:22]=[C:23]([S:46][CH2:18][C:16]2[N:13]=[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=3)[S:12][CH:15]=2)[C:24]([C:44]#[N:45])=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]3[CH2:41][O:40][C:39]([CH3:42])([CH3:43])[O:38]3)=[CH:31][CH:30]=2)[C:26]=1[C:27]#[N:28]
Reactant: O=C(CCl)CCl
Reactant: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Reactant: NC(=S)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(SCc4csc(Nc5ccc(C(=O)O)cc5)n4)c3C#N)cc2)O1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
177 mg (0.90 mmol) of 4-carboxyphenylthiourea and 111 mg (0.87 mmol) of 1,3-dichloroacetone are dissolved in 3 ml of DMF, and the reaction solution is stirred at 100° C. for 60 min. After cooling, 230 mg (0.60 mmol) of the compound from Example 3A and 151 mg (1.80 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 16 h. The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C(OC([C:8]1([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25].FC(F)(F)C(O)=O>ClCCl>[NH2:14][CH:8]1[CH2:9][CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C1(N)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of 4-amino-piperidine-4-carboxylic acid tert-butyl ester (2.50 g; 12.5 mmol) and Huenigs base (3.2 mL) in dichloromethane (15 mL) is added acetyl chloride (1.1 mL; 15.0 mmol) under ice-cooling. The mixture is stirred overnight at ambient temperature. The solvent is evaporated and the obtained crude is partitioned between ethyl acetate and 1M aqueous HCl. Drying and evaporation of the solvent gave an orange oil which is dissolved in dichloromethane (38 mL). Trifluoroacetic acid (19 mL) is added and the mixture is stirred for 20 min at ambient temperature. The volatiles are completely evaporated at 35° C. bath temperature and the obtained residue is dissolved in a mixture of dichloromethane/methanol (95:5 v/v). Solid sodium carbonate is added and the suspension is stirred at ambient temperature overnight. Filtration and evaporation of the solvent gave 0.98 g of the title compound as slightly brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:8][C:9]#N)[CH:7]=1.S(=O)(=O)(O)[OH:13].[OH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:8][C:9]([OH:13])=[O:17])[CH:7]=1
Reactant: O
Reactant: N#CCc1cc(Br)ccc1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)Cc1cc(Br)ccc1Cl
Temperature: 160 °C

Procedure:
The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccn3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.012 g, 0.039 mmol) in tetrahydrofuran (0.1 mL) and water (0.0285 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.047 mmol) at room temperature and stirred for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1 N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C14H15N4OS (M+H)+: m/z=287.1. Found: 287.0.
Reaction SMILES: [Na].C(O)C.Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25](=O)[C:26]#[C:27][CH3:28])=[C:20]2[CH:19]=[CH:18][CH:17]=1>O>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]3[CH:26]=[C:27]([CH3:28])[N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)NC1CCCC1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a dry round bottom flask was added sodium metal (81 mg, 3.5 mmol). Ethanol (20 mL) was added and allowed to react with sodium at room temperature until completely dissolved. N-Cyclopentylguanidine hydrochloride (572 mg, 3.5 mmol) was added and the mixture was allowed to stir at room temperature for 10 minutes. To the resultant mixture was added 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (842 mg, 2.69 mmol) and the reaction mixture was allowed to stir at room temperature for 72 hours, then heated to 70° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ether to 3:2 hexanes:ether) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (1.11 g, 98%) as a yellow foam. Rf 0.45 (3:1 hexanes:ethyl acetate). 1H NMR (CDCl3) δ 8.35 (d, 1H), 7.64 (m, 2H), 7.24 (m, 1H), 7.13 (m, 2H), 7.03 (d, 1H), 6.22 (s, 1H), 5.10 (m, 1H), 4.35 (m, 1H), 2.19 (s, 3H), 2.03 (m, 2H), 1.60 (m, 6H); MS m/z 422 (M+1).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].O.[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[OH:28])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22][C:21]2=[O:31]>>[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH:12]([CH3:14])[CH3:13])[O:24][C:23]([CH3:29])([CH3:30])[CH2:22][C:21]2=[O:31]
Reactant: CC(C)I
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc2c(cc1O)C(=O)CC(C)(C)O2
Temperature: 130 °C
Yield: 90 %

Procedure:
In 80 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 130° C. for 6 hours, poured into 200 ml of water and extracted with 100 ml of carbon tetrachloride. To the aqueous layer 50 ml of an 5% sodium hydroxide solution are added and the mixture is cooled below 5° C. The mixture is acidified with concentrated hydrochloric acid, the precipitated crystalline substance is filtered off and crystallized from methanol. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 138°-139° C.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.N1C=CC=CC=1.[C:24]1([C:30]2([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:33]1[CH2:32][CH2:31][C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)C1(c2ccccc2)CCN(CCCC(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydro-carbostyril, 12 g of pyridine and 2.7 g of 4-phenyl-4-acetyl-piperidine were mixed in 30 ml of dimethylformamide and stirred at 70°-80° C. for 7 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate aqueous solution and the organic layer was extracted with chloroform then the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 6-[1-oxo-4-(4-phenyl-4-acetyl-1-piperidyl)butyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Yield: 2.1 g.
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>>[ClH:33].[CH3:1][N:2]([CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](=[NH:38])[NH2:22])=[CH:19][CH:20]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: [NH4+]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C(=N)N)cc2)n3C)CC1

Procedure:
Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide with ethanolic hydrochloric acid and ammonium carbonate. Yield: 370 mg (83% of theory), C23H30N6O3S (470.6) ##EQU13##
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:29](=[O:31])=[O:30]>CCOCC>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:29]([OH:31])=[O:30])=[CH:12][C:11]([Cl:14])=[N:10][CH:9]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 35 %

Procedure:
A stirred solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (3.28 g, 14.3 mmol) and TMEDA (6.7 mL, 44.4 mmol) in Et2O (100 mL) at −78° C. was treated with n-BuLi (4.3 mL, 10 M, 43 mmol). After stirring the mixture at −78° C. for 2 hours CO2 was bubbled into the reaction and the solution was warmed to 0° C. Water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified and extracted with Et2O. The Et2O layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The residual solid was triturated with Hexane/Et2O to give 25A (1.38 g, 35%) HPLC Rt=2.98 min.