Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccccc2)CC2CCC1N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol (0.1 g, 0.34 mmol) was dissolved in TFA (1 mL) and cooled to 0° C. Concentrated sulphuric acid (0.054 mL) was added and the mixture stirred for 1 hour, then triethylsilane (0.17 mL) was added. After 2 hours the mixture was allowed to warm to room temperature, and then to stand for 60 hours. The mixture was concentrated under vacuum and diluted with a solution of saturated aqueous sodium carbonate. The products were extracted into DCM, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a colourless oil. LCMS m/z 276.5 [M+H]+. R.T.=2.94 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:23].[CH:24]1([C:27]2[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:30]2[N:31]=[C:27]([CH:24]3[CH2:26][CH2:25]3)[S:28][CH:29]=2)=[O:15])=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)ccc1Cl
Reactant: NCc1csc(C2CC2)n1
Product: Cc1cc(-c2cc(C(=O)NCc3csc(C4CC4)n3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BJ) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9) as starting materials; LC-MS (UV peak area/ESI) 95.4%, 482.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](O)=[O:17].CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[I:44][C:45]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1>C(Cl)Cl>[I:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])=[CH:47][CH:46]=1
Reactant: Nc1ccc(I)cc1
Reactant: COc1cccc(Cn2c(C(=O)O)cc3ccccc32)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Cn2c(C(=O)Nc3ccc(I)cc3)cc3ccccc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg 1-(3-Methoxy-benzyl)-1H-indole-2-carboxylic acid in 8 ml DCM and 0.9 NEt3 452 mg, BOP-Cl was added at RT and the mixture was stirred for 30 min. After addition of 583 mg 4-Iodo-phenylamine the mixture was stirred for 16 h. Then the solvent was removed under reduced pressure to yield a white precipitate, which was washed with 1 ml MeOH/DCM 1:1.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11]I)=[O:8])(=[O:4])=[O:3].[N-:17]=[N+:18]=[N-:19].[Na+]>C(O)C>[NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][N:17]=[N+:18]=[N-:19])=[O:8])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccccc1C(=O)OCCI
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A mixture of 1.6 g of the product from Example 2 and 0.3 g of sodium azide in 10 mL absolute ethanol was heated at reflux temperature for 24 hours. Additional sodium azide (0.3 g) was added and the suspension was heated for another 24 hours. The reaction mixture was cooled to room temperature and the ethanol was removed in vacuo. The resultant crude oil was purified by careful chromatography on silica gel. Elution with 1:1 hexane/ethyl acetate gave 0.5 g of the desired product as a colorless, viscous oil; IR (film): 1720, 2100 cm-1 ; NMR (CDCl3): δ 3.67 (t, 2H, J=4 Hz), 4.55 (t, 2H, J=4 Hz), 5.77 (br s, 2H), 7.65 (m, 2H), 7.9 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25]([NH2:27])=[N:24][CH:23]=[N:22][C:21]=3[N:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)=[CH:14][C:13]=1[O:33][CH3:34].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:27][C:25]1[C:26]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:13]([O:33][CH3:34])[CH:14]=3)=[CH:19][N:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)NCc1ccccc1
Reaction time: 24 h

Procedure:
Benzylisocyanate (24 uL, 0.194 mmol) in dichloromethane (1 mL) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in N,N-diisopropylethylamine (153 uL, 0.881 mmol) and methylene chloride (2 mL) under nitrogen. The resulting mixture was stirred for 24 hours. The solvent was evaporated and the solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give N-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-N′-benzylurea. 1H NMR (CDCl3) δ 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.86 (s, 3H), 4.48 (d, J=6 Hz, 3H), 5.24 (m, 4H), 6.93 (s, 1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=8 Hz, 1H), 7.29 (m, 5H), 8.17 (d, J=8 Hz, 1H), 8.31 (s, 1H); LC/MS (MH+=457).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:33])[CH:7]=[C:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1ccccc1
Temperature: 95 °C

Procedure:
To a stirred solution of 9-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoic acid tert-butyl ester 29-6 (100 mg, 0.20 mmol) in toluene (2.5 mL) was added palladium(tetrakis)-triphenylphosphine (23 mg, 0.020 mmol), phenylboronic acid (50 mg, 0.41 mmol), and potassium carbonate (56 mg, 0.41 mmol). The resulting suspension was heated at 90-100° C. for 2 hours, and then was allowed to cool to ambient temperature. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 4:1 ethyl acetate/hexanes to give 29-7a as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([OH:37])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45](Br)[CH:46]=[CH2:47]>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:47]([O:37][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=1)[C:24]([NH:23][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:12])=[O:38])[CH:46]=[CH2:45]
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-[(1S,2S,4R)-1-Benzyl-4-(3,3-bimethylbutylcarbamoyl)-2-hydroxypentyl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzamide (E2) (0.061 g, 0.117 mmol), caesium carbonate (0.050 g, 0.152 mmol) and allyl bromide (0.016 ml, 0.176 mmol) in DMF (1 ml) was stirred vigorously at room temperature for 2 hrs. More allyl bromide (0.008 ml) was added and stirring was continued for a further 1 hr. The mixture was diluted with ethyl acetate and 2N HCl and the product was extracted into ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (elution with 2–5% methanol in dichloromethane) gave the product, 0.047 g.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35]>C(#N)C>[CH2:34]([N:36]([CH2:40][CH3:41])[C:37]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:38])[CH3:35]
Reactant: CCN(CC)C(=O)Cl
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.4 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.40 g, 1.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and acetonitrile (20 ml) was stirred at room temperature for 20 minutes. Successively N,N-diethylcarbamoyl chloride (0.54 g, 4.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (30:1, v/v) were collected, concentrated and recrystallized from ethanol-hexane to give the titled compound (0.12 g, 31%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]=[CH:22][CH:23]=4)=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:32].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=4)[NH2:24])=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:32].[C:35]([OH:37])([C:34]([F:39])([F:38])[F:33])=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)carbamate (10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was stirred overnight at RT. The mixture was concentrated to afford the desired product as a TFA salt which was directly used for next step. LCMS: (M+H)=397.9/399.9.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.[C:15]([C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23])#[N:16].Cl>ClCCl>[Cl:8][C:5]1[S:4][C:3]([NH:2][S:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([C:15]#[N:16])[CH:18]=2)(=[O:25])=[O:26])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-amino-5-chlorothiazole-hydrochloride (3.76 g, 22.0 mmol) in dichloromethane (20 ml) was added pyridine (8.09 ml, 100 mmol). 3-cyano-4-fluorobenzenesulfonyl chloride (4.39 g, 20 mmol) dissolved in dichloromethane (5 mL) and was added to the reaction mixture dropwise at room temperature. After stirring for 48 hours at room temperature, 1 N HCl (100 mL) was poured into the reaction and the mixture was extracted with dichloromethane/methanol (v/v=95/5, 100 ml) three times. The collected organic layer was evaporated in vacuo and dried over MgSO4 to obtain the crude residue. The crude residue was washed with dichloromethane (10 mL) and filtered to afford pale yellow solid as the title compound. LCMS Rt=1.39 minutes MS m/z 318 [M35ClH]+, 320 [M37ClH]+ 1HNMR (d6-DMSO): δ 7.59 (s, 1H), 7.66-7.73 (m, 1H), 8.15-8.21 (m, 1H), 8.33-8.37 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:23][F:24])([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:4]#[C:5][C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7]>ClC1C=CC=CC=1Cl>[F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:4]=[C:5]([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[C:18]2[CH:17]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:14][C:13]=2[O:12]1
Reactant: CCCNC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Solvent: Clc1ccccc1Cl
Product: CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Yield: 62 %

Procedure:
An amount (50 mg) of 5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-N-propyl-2-pentynamide was dissolved in o-dichlorobenzene (5 ml) and the solution was heated under reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to give the titled compound (31 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][N:16]=[N:15][C:14]=1[CH3:19].C[S-].[Na+]>CN(C)C=O>[CH3:19][C:14]1[N:15]=[N:16][CH:17]=[CH:18][C:13]=1[C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(C(F)(F)F)cc1-c1ccnnc1C
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnccc1-c1cc(C(F)(F)F)ccc1O
Temperature: 70 °C
Yield: 53.3 %

Procedure:
To a solution of 4-[2-methoxy-5-(trifluoromethyl)phenyl]-3-methylpyridazine (Preparation 43, 650 mg, 2.4 mmol) in N,N-dimethylformamide (18 mL) was added sodium thiomethoxide (850 mg, 12 mmol) and reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was then cooled to 0° C., poured onto ice water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (5×100 mL) and saturated aqueous sodium chloride solution (100 mL) then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (20% ethyl acetate in heptane elution) to afford the title compound as a yellow solid (325 mg).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]2[C:16](=[O:26])[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][C:12]=2[NH:11][C:10]=1[CH3:34])=[O:8].[H][H]>[Pd].CO>[CH3:2][O:3][CH:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]2[C:16](=[O:26])[CH2:15][NH:14][CH2:13][C:12]=2[NH:11][C:10]=1[CH3:34])=[O:8]
Reactant: COC(COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1cccc(Cl)c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1cccc(Cl)c1)c1ccccc1
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A mixture of 15.3 g of 1-benzyl-3-hydroxy-5-oxo-2,3,4,6-tetrahydropyridine hydrate, 10.6 g of 3-chlorobenzaldehyde, 17.7 g of 2-methoxy-2-phenylethyl acetoacetate, 12 g of ammonium acetate and 150 ml of methanol was refluxed for 5 huors. The solvent was removed in vacuo. The residue was dissolved in methylenechloride, extracted with water, then dried over magnesium sulfate. The solution was diluted with diethyl ether to the point of cloudiness, then left at room temperature for 18 hours. The supernatant was decanted and the precipitate was slurried with ethanol and filtered to obtain 12.9 g of the solid, mp. 168°-170° C. dec. The solid was suspended in methanol and saturated with hydrogen chloride. The mixture was cooled in an ice bath, then filtered. The solid was recrystallized from ethanol to obtain 11.1 g of 4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-7-(phenylmethyl)-1,7-naphthyridine-3-carboxylic acid 2-methoxy-2-phenylethyl ester hydrochloride, mp. 222°-4° C. dec. The hydrochloride (10.8 g), 1 g of 10% palladium on carbon and 450 ml of methanol were shaken with hydrogen at an initial pressure of 48.5 psig. After 4 hours, the catalyst was separated and the solution was evaporated to dryness The residue was dissolved in methanol, saturated with hydrogen chloride, then evaporated to dryness. The residue was recrystallized from ethanol to obtain 3 g of the title compound as the hydrochloride, monohydrate, mp. 165°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:42])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:22])=[C:17]([CH2:34][O:35]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:42])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:22])=[C:17]([CH2:34][OH:35])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2COCC[Si](C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2CO)c1
Yield: 105.2 %

Procedure:
A solution of 157 mg of N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3-6% MeOH in CH2Cl2 provides 140 mg of the title compound as a white solid. Recrystallization from acetonitrile affords white crystals.
Reaction SMILES: CCC([O-])(C)C.[Na+].[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[C:21]=1[F:30].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:30][C:21]1[C:20]([F:19])=[CH:25][CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[C:22]=1[CH:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CCC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(F)c1F
Temperature: 40 °C

Procedure:
To toluene (810 l) was charged sodium tert-pentoxide (91 kg, 2.3 eq). The mixture was heated to 40° C. and tert-butyl acetoacetate (124.3 kg, 2.2 eq) added. The mixture was heated to 70° C. and trifluoronitrobenzene (63.1 kg, 1.0 eq) added. The temperature was maintained at 70° C. for 3 hours. The mixture was cooled to 25° C. and 20% w/w sulphuric acid added to adjust the pH to 5. The lower aqueous layer was discarded and the organic layer washed twice with water (2×227 kg of water), with 2.3% w/w sodium bicarbonate (192 kg) and then water (192 kg). The organic layer was distilled under vacuum (50 mbar), removing 574 kg of distillate leaving a solution of tert-butyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in toluene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:25])[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH:18]([CH3:25])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1CNC(C)c2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1CN(C(=O)c2cc3ncc(Br)cn3n2)C(C)c2ccccc21

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-chloro-3-fluoro benzoic acid (450.0 g, 2.586 mol, Fluororochem, Derbyshire, UK) in methanol (4.5 L) was cooled to 0° C. and thionyl chloride (450.0 mL) was added over 30 minutes. The reaction mixture was stirred for 12 hours at ambient temperature. The reaction was monitored by TLC. Upon completion, the solvent was removed under reduced pressure and the residue was quenched with 1.0 M sodium bicarbonate solution (500 mL). The aqueous layer was extracted with dichloromethane (2×5.0 L). The combined organic layer was washed with brine (2.5 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure afforded the title compound as light brown solid. The crude compound was used in the next step without further purification.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH3:24])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH2:26]>C(OCC)(=O)C>[CH2:28]([O:27][CH:25]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH3:24])=[O:22])[CH3:26])[CH:29]([CH3:31])[CH3:30]
Reactant: C=COCC(C)C
Reactant: COC(=O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)OC(C)OCC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 20.8 g (0.2 mole) of methyl (R)-(+)-lactate and 22.0 g (0.22 mole) of isobutyl vinyl ether. The resulting mixture was stirred at room temperature for 3 hours to give rise to a reaction. Thereto was added 100 ml of ethyl acetate, followed by washing with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 38.8 g (yield: 95.1%) of an oily title compound (diastereomixture).