Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:28])[C:16]([O:26][CH3:27])([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)N.Cl(O)(=O)(=O)=O.[NH:34]=[N+:35]=[N-:36]>O1CCCC1.C(Cl)Cl>[N:34]([CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:28])[C:16]([O:26][CH3:27])([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=N
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(COC(N)=O)=CS[C@@H]21
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(CN=[N+]=[N-])=CS[C@@H]21
Reaction time: 9 h

Procedure:
A mixture of the benzhydryl ester of 3-carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.212 g.), perchloric acid (0.36 g.) in tetrahydrofuran (6.0 ml.) and hydrazoic acid (28.0 ml., 0.18 N) in methylene chloride is stirred under a nitrogen atmosphere for nine hours. The reaction mixture is washed with a 5% aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation. The crude product is purified by chromatographing through a column of silica gel G to yield the substantially pure benzhydryl ester of 3-azidomethyl-7-methoxy-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid.
Reaction SMILES: S([NH:11][C@H](C(O)=O)CC1N=CNC=1)(C1C=CC(C)=CC=1)(=O)=O.N[C@H:23]([C@@H:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:11][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:23][CH:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)CC(O)CC(N)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 202.4 %

Procedure:
To a solution of Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidine (195 mg) and (2S,3S)-2-amino-1-cyclohexyl-3-hydroxy-5-methylhexane (82 mg) in dry methylene chloride (10 ml) which was cooled at 0° C., was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (72 mg). The mixture was stirred at 0° C. for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml) and the solution was washed with 10% citric acid solution, saturated sodium bicarbonate solution, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:n-hexane, 2:3, V/V, as eluent) to give (2S,3S)-2-(Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidyl)amino-1-cyclohexyl-3-hydroxy-5-methylhexane (166 mg) as an amorphous powder. Rf: 0.29 (ethyl acetate:n-hexane, 3:2, V/V)
Reaction SMILES: [O:1]([CH2:8][C:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(3-(N-ethoxycarbonyl)-4-chlorobenzenesulfonamido]-2-(3-pyridyl)}propyl]phenoxyacetate (181 mg) was dissolved in 2 ml of ethanol, followed by addition of 2 ml of aqueous 1N sodium hydroxide solution, and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 1N hydrogen chloride for neutralization, and the deposited crystalline was filtered to obtain 89 mg of [3-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)}propyl]phenoxyacetic acid. The spectrometric data supports the structure of [34] as follows.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].BrCCC=C.O>O1CCCC1>[CH3:2][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: CCc1ccccn1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(C)c1ccccn1
Temperature: -20 °C

Procedure:
A solution of 8.46 ml (0.074 mol) of 2-ethylpyridine in 35 ml of tetrahydrofuran was cooled to −20° C. and 47 ml of n-butyllithium (15 w.-% in hexane, 0.074 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled back down to −20° C. A solution of 7.52 ml (0.074 mol) of 4-bromo-1-butene in 10 ml of tetrahydrofuran was then added at such a rate that the temperature remained at −20° C. The mixture was allowed to warm to room temperature, stirred for a further 14 hours and hydrolyzed with 50 ml of water. The organic phase was separated off and the aqueous phase was extracted three times with 30 ml each time of diethyl ether. The organic phases were combined; dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The residue obtained in this way was distilled at 98-100° C./14 torr. This gave 8.95 g (75%) of 2-(1-methyl-4-pentenyl)pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (3.17 g, 20 mmol), morpholine (2.00 g, 23 mmol) and Et3N (2.43 g, 24 mmol) in EtOAc (200 mL) was refluxed for 3 h, then cooled to rt, and washed with water (100 mL×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (3.89 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18]C)[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(-c3cccc(Cl)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(O)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 2-[3-(3-chlorophenyl)-7-methoxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (886 mg, 2.30 mmol) in dry DCM (25 mL) was cooled to −78° C. and a solution of BBr3 (1 M in DCM, 20.3 mL, 20.3 mmol) was added dropwise. After 1 h, the cooling bath was removed and the mixture was allowed to stir an additional 17.5 h, then cooled to 0° C. and quenched by dropwise addition of sat. NaHCO3 (aq.) (15 mL). The aqueous mixture was extracted with IPA:DCM (1:3, v/v) (4×25 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated to give the crude product, which was recrystallized from EtOH to give pure 2-[3-(3-chlorophenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (INTERMEDIATE III.7) (530 mg, 1.43 mmol, 62%) as white solid.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: O=Cc1cccc(F)c1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cccc(F)c2F)cc1OC
Yield: 90 %

Procedure:
2,3-Difluorobenzaldehyde (426 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (813 mg, yield: 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH3:5][Si:6]([CH3:21])([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]1[CH2:14][O:13]1>C(O)C>[CH3:5][Si:6]([CH3:21])([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:13])[CH2:14][NH:1][CH2:2][CH2:3][OH:4]
Reactant: NCCO
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCO
Temperature: 70 °C

Procedure:
2-Amino-ethanol (2.22 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess 2-amino-ethanol.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80136.6 %

Procedure:
A mixture of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (35 g, 0.087 mmol)) and Pd/C (3.5 g) in ethyl acetate (400 ml) was hydrogenated under a pressure of 80 psi for 2 h. The reaction mixture was filtered off and filtrate concentrated under vacuum to give tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate (28 g) as a liquid. Yield: 80%
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4([CH3:22])[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[C:3]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4([CH3:22])[CH2:20][CH2:21]4)=[CH:13][CH:14]=3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1N1C(=O)c2cc(C3(C)CC3)ccc2CC1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2ccc(C3(C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-hydroxy-7-(1-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one (1.134 g, 2.2 mmol) was dissolved in 13 ml dichloromethane at room temperature; triethylamine (1.31 ml, 9.44 mmol) followed by addition of methanesulfonyl chloride (0.478 g, 4.171 mmol) were added. It was stirred for 1.5 hours at room temperature but it's already done in 10 minutes according to LCMS. The reaction mixture was extracted with dichloromethane/water; organic phase was washed with brine; dried over sodium sulfate; filtered; concentrated to give 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-7-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one (1.094 g, 2.2 mmol) MS (ESI) 520.0 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.C(N(CC)CC)C.[CH2:21]([S:25](Cl)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:21]([S:25]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Oc1cn(C)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-1-methyl-4-quinolone (3 g) was suspended in dichloromethane (200 ml), triethylamine (5.6 ml) was added to the suspension and the mixture was stirred at ambient temperature for hour. 1 -Butanesulphonyl chloride (2.6 ml) was added to the suspension, the mixture stirred for 90 minutes and then left to stand overnight. The resultant mixture was washed with water (400 ml), aqueous sodium hydroxide (1M, 400 ml) and then further water (3×300 ml). The dichloromethane layer was dried over magnesium sulphate and evaporated to give a solid which was crystallised from methanol (100 ml) to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinol-3-yl 1-butanesulphonate, m.p. 143°-144°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][OH:12].C1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:12][CH2:11][CH2:10][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C

Procedure:
29.54 g (151.5 mmol) of bromoacetic acid-tert-butyl ester is added in drops to a mixture of 20 g (75.73 mmol) of 1H,1H,2H,2H-perfluorohexan-1-ol and 2.57 g (7.57 mmol) of tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassium hydroxide solution/200 ml of toluene while being stirred vigorously at 0° C. It is stirred for 1 hour at 0° C. 100 ml of toluene is added, the aqueous phase is separated and extracted twice with 50 ml of toluene. The combined organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichloromethane/acetone=20/10/1).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29](C2C=CC=CC=2)[CH2:28][CH2:27]1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].BrCCCCCCN([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1OC(C)(C)C)CCNC(=O)OC(C)(C)C.C(C1CCNCC1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:30][CH2:31]1)[CH2:8][C:7]1[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=1[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(CC2CCNCC2)cc1
Product: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(Cc2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Yield: 58 %

Procedure:
The same procedure as described for compound 16 was applied to starting material 15 (2.4 g, 5.89 mmol), 4-benzylpiperidine (2.06 g, 11.78 mmol) and K2CO3 (0.814 g, 5.89 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2. The product was isolated as pale yellow oil (58%). 1H NMR (CDCl3) δ 7.328 (dd, 1H, Ar), 7.211 (t, 2H, Ar), 7.132 (t, 1H, Ar), 7.077 (m, 3H, Ar), 6.951 (m, 2H, Ar), 3.576 (s, 2H, —CH2—), 3.302 (d, 2H, —CH2—), 3.112 (m, 2H, —CH2—), 2.729 (m, 2H, —CH2—), 2.525 (m, 6H), 2.395 (m, 2H, —CH2—), 1.819 (m, 2H, —CH2—), 1.724 (m, 5H), 1.424 (m, 2H, —CH2—), 1.356 (s, 9H, —C(CH3)3), 1.325 (s, 9H, —C(CH3)3), 1.224 (s(br), 4H, —CH2—CH2—). Mass Spec.=579.86 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][NH:28][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:32][CH2:31]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NCC1CC1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NCC3CC3)cn2)cn1
Yield: 47 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (40 mg, 47%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC). MS: m/e=418.3 [M+H]+.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.C1COCC1.CO.[OH-].[Na+]>C(OCC)(=O)C>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH2:8][OH:7])([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate from above reaction was added THF:MeOH (1:1, 2 mL) and 2M NaOH (0.5 mL) were added and reaction mixture was heated at 55° C. for 3 h. Reaction mixture was cooled to rt, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (EtOAC/Hex) to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethanol (15 mg). LCMS-ESI+: calc'd for C33H32ClN4O2S: 583.2 (M+H+); found: 583.3 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][CH:13]([N:17]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH3:18])[CH2:12][C:11]=2[C:10]2[N:29]=[CH:30][CH:31]=[CH:32][C:9]1=2)(C)(C)C.CO.[OH-].[Na+].Cl>C1COCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:17]([CH3:18])[CH:13]2[CH2:14][CH2:15][C:16]3[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]4[CH:32]=[CH:31][CH:30]=[N:29][C:10]=4[C:11]=3[CH2:12]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: CN(C1CCc2c(c3ncccc3n2CC(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CCc2c(c3ncccc3n2CC(=O)O)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 24 h
Yield: 10.6 %

Procedure:
A solution of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid tert-butyl ester (43 mg, 0.9 mmol) was dissolved in THF (1 mL), MeOH (1 mL) and 1N NaOH (0.2 mL). After 24 hours, the reaction mixture was neutralized with 1N HCl and concentrated to afford 40 mg of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid. Mass spectrometric data [M+H]+=418.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:16]=[C:15]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([CH3:23])=[CH:13][C:11]=1[NH2:12]>C1(C)C=CC=CC=1>[CH3:5][N:4]([CH3:6])[CH:3]=[N:12][C:11]1[CH:13]=[C:14]([CH3:23])[C:15]([C:17]#[C:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:16][C:10]=1[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(C#C[Si](C)(C)C)c(C)cc1N
Solvent: Cc1ccccc1
Product: Cc1cc(N=CN(C)C)c(C)cc1C#C[Si](C)(C)C
Temperature: 110 °C
Reaction time: 9 h
Yield: 41 %

Procedure:
N,N-dimethylformamide dimethyl acetal (5.97 g) and 10 ml of toluene were added to 1.09 g of the 2,5-dimethyl-4-(2-trimethylsilyl-1-ethynyl)aniline (Compound 4-27) produced in Production Example 3, and the mixture was stirred at 110° C. for 9 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), thereby obtaining 0.56 g of N,N-dimethyl-N′-[2,5-dimethyl-4-(2-trimethylsilyl-1-ethynyl)phenyl]formamidine (Compound 59).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:34])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
353 mg (1.06 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 137 mg (1.06 mmol) of ethyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 245 mg (52% of theory) of the title compound as a yellow solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][O:35]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25]C(=O)C1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][OH:35])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of nucleoside 61 (0.80 g, 1.42 mmol) in anhydrous dichloromethane (30 cm3) at −78° C. was dropwise during 30 min added BCl3 (1 M solution in hexane; 11.36 cm3, 11.36 mmol). The mixture was stirred for 4 h at −78° C., additional BCl3 (1 M solution in hexane, 16.0 cm3, 16.0 mmol) was added drop-wise, and the mixture was stirred at −78° C. for 3 h. Then the temperature of the reaction mixture was raised slowly to room temperature and stirring was continued for 30 min. Methanol (25.0 cm3) was added at −78° C., and the mixture was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane/-methanol (92:8, v/v) as eluent to give nucleoside 61A as a white solid material (0.332 g, 84%). δH ((CD3)2SO) 8.22 (1H, s, 8-H), 8.15 (1H, s, 2-H), 7.33 (2H, s, NH2), 5.89 (1H, s, 1′-H), 5.83 (1H, d, J 4.2, 3′-OH), 5.14 (1H, t, J 5.9, 5′-OH), 4.14 (1H, s, 2′-H), 4.25 (1H, d, J 4.2, 3′-H), 3.92 (1H, d, J 7.8, 1″-Ha), 3.81-3.41 (3H, m, 5′-Ha, 5′-Hb, 1″-Hb). δC ((CD3)2SO) 155.90 (C-6), 152.64 (C-2), 148.35 (C-4), 137.72 (C-8), 118.94 (C-5), 88.48, 85.17 (C-1′, C-4′), 79.09, 71.34, 69.83, 56.51 (C-2′, C-3′, C-1″, C-5′). FAB-MS m/z 280 [M+H]+.