Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][N:23]=[C:24]1[C:28]2([CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)[CH2:27][NH:26][CH2:25]1>C(#N)C>[C:35]([O:34][C:32]([N:30]1[CH2:31][C:28]2([C:24](=[N:23][O:22][CH3:21])[CH2:25][N:26]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:16])[CH2:27]2)[CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 43.7 %

Procedure:
150 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 320 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was refluxed for 7 hours and then cooled to room temperature. The precipitated solid was filtered and dried to give 120 mg of the titled compound(yield: 55.5%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCCO)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCO)cc(Br)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 173.5 %

Procedure:
To a solution of 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (5.40 g, 28.09 mmol) in anhydrous DMF (56 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (3.96 g, 13.9 mmol, 0.50 eq) proportionwise at −50° C. The reaction mixture was warmed to 0° C. and stirred at 0° C. for 2 h. The reaction mixture was quenched with water and poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Crystallization from DCM afforded 6.54 g (85.9%) of the desired product as a beige solid. 1H-NMR (DMSO-d6) 7.83 (s, 1H), 6.61 (s, 1H), 4.52 (broad s, 1H), 3.41 (t, 2H), 2.83 (t, 2H), 1.75 to 1.77 (m, 2H); MS LC-MS [M+H]+=271/273, RT=1.40 min.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)[C:13]2=[O:28])[CH:9]=[CH:8][C:7]=1[O:29][C:30]([F:33])([F:32])[F:31])=[O:4].[NH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:40][C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:22]=3)[C:13]2=[O:28])[CH:9]=[CH:8][C:7]=1[O:29][C:30]([F:33])([F:32])[F:31])=[O:4]
Reactant: Nc1cccnc1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)[C@H](N)c3ccccc3)c2)C(=O)N1Cc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)[C@H](N)c3ccccc3)c2)C(=O)N1Cc1ccnc(Nc2cccnc2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 33 mg of (2R)-2-amino-N-[5-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-(trifluoromethoxy)phenyl]-2-phenylacetamide obtained in stage d) below in 1 mL of dioxane are successively added, under argon, 7 mg of 3-aminopyridine, 3 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 1.1 mg of palladium acetate and 61 mg of caesium carbonate. The reaction mixture is heated at 110° C. for 1 hour, filtered and washed with twice 10 mL of dioxane, and the filtrate is then concentrated under reduced pressure. The residue is taken up in 1 mL of dioxane, 1 mL of a 4N solution of hydrogen chloride in dioxane is then added and the reaction mixture is stirred at 40° C. for 2 hours. The reaction mixture is then treated with 30 mL of saturated sodium hydrogen carbonate solution and extracted with three times 30 mL of ethyl acetate. The combined organic phases are then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 12 mg of (2R)-2-amino-N-[5-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)-2-(trifluoromethoxy)phenyl]-2-phenylacetamide, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:35](O)([CH3:37])[CH3:36]>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([O:6][CH:35]([CH3:37])[CH3:36])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)OC(C)C)c1

Procedure:
A solution of the title product of Example 4 (6.2 mmole) and sulfuric acid (0.5 ml) in 120 ml of isopropyl alcohol (100 ml) was heated at 45° C. for 12 days, refluxed for 36 hours, and concentrated on a rotary evaporator to an oil. The oil was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound, m.p. 72°-73° C.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](OCC)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:2]([NH:4][C:22]([CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1)=[O:23])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Ethylamine hydrochloride (6.59 g, 80.8 mmol) is dissolved in 40 ml dry toluene and cooled to 0°. Trimethylaluminum (2M in toluene, 40.4 ml, 80.8 mmol) is slowly added and after 30 min at 0° the mixture is warmed to 20°-25°. After one hr gas evolution has ceased. Then ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol) is added in 20 ml of toluene and the mixture is heated to 85° for 2 hr. The reaction is quenched cautiously with 5% hydrochloric acid, then adjusted to pH 8 with sodium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to give the title compound; NMR (300 MHz, CDCl3) 7.32, 3.58, 3.27, 3.00, 2.0-2.2, 1.7-2.0 and 1.11δ.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Yield: 72.4 %

Procedure:
In a similar fashion using route 7 general procedure 15, 5-chloroquinoline (1 g, 6.13 mmol), potassium nitrate (800 mg, 7.98 mmol) and H2SO4 (3 ml) and gave the title compound (926 mg, 73%). The structure was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[F:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:34][CH2:33][C:32](=O)[CH2:31]2)[CH:27]=[CH:28][CH:29]=1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CCOC(C)=O.CCCCCCC.C(Cl)Cl.O1CCCC1.CO>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:33]2[CH2:32][CH2:31][CH:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)[CH2:34]2)=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(c2cccc(F)c2)C1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1NC1CCC(c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
A 40-mL vial was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (1.2 g, 3.73 mmol) and 3-(3-fluorophenyl)cyclopentanone (665 mg, 3.73 mmol) then purged with nitrogen for 10 min. Methanol (16.0 ml), tetrahydrofuran (4.0 ml), and acetic acid (1.89 ml, 33.0 mmol) were sequentially introduced. Sodium cyanoborohydride (469 mg, 7.46 mmol) was then added in a single portion to the yellow reaction mixture. The vial was sealed with a PTFE line cap and the solution stirred vigorously at ambient temperature. After 16 h, the reaction mixture was heated to 50° C. After 22 h, the reaction mixture was allowed to cool to ambient temperature and carefully poured into a mixture of ice and a saturated aqueous solution of sodium bicarbonate. The mixture was stirred until, it reached ambient temperature then it was diluted with EtOAc (30 mL) and the layers were separated. The aqueous layer was further extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (50-g Biotage column, eluent: gradient, 20 to 70% EtOAc in heptane with CH2Cl2 as a 10% additive) to afford (E)-ethyl 3-(5-(benzylthio)-2-((3-(3-fluorophenyl)cyclopentyl)amino)phenyl)acrylate (812 mg, 1.707 mmol, 45.8% yield) as a yellow solid. m/z (ESI) 476.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[C:5]([C:13](OC)=[O:14])[CH:4]=1)#[N:2].[BH4-].[Li+].C([O-])(O)=O.[Na+]>CCO.C1COCC1>[OH:14][CH2:13][C:5]1[C:6]([CH2:9][OH:10])=[CH:7][N:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1cnc(C#N)cc1C(=O)OC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(CO)c(CO)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of dimethyl 6-cyanopyridine-3,4-dicarboxylate (2.00 g, 9.08 mmol) [Hashimoto et al. (1997) Heterocycles 46, 581] in EtOH (50 mL) was added lithium borohydride (4.54 mL of a 2 M solution in THF, 9.08 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 h, and then cooled to 0° C. Saturated aqueous NaHCO3 (20 mL) was added slowly and the quenched mixture was extracted with EtOAc (9×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 85:15, to give the title compound. MS: m/z=165 (M+1).
Reaction SMILES: ClCl.[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([SH:22])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1.[C-:24]#[N:25].[K+]>C(O)(=O)C.ClCCl>[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([S:22][C:24]#[N:25])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: [C-]#N
Agent: ClCl
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
At 20° C., chlorine gas is introduced into a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 0.65 g (10 mmol) of potassium cyanide in 20 ml of acetic acid. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with dichloromethane. The mixture is then extracted repeatedly with dilute aqueous sodium hydroxide solution and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product that remains is purified over silica gel using petroleum ether/ethyl acetate=1:1 as mobile phase. Concentration of the eluate gives 1.2 g (64% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-thiocyanato-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:47])[C:21]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>CO>[C:20]1([CH3:47])[C:21]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C(N)c1ccccc1
Agent: Cc1ccccc1C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c1ccccc1C
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1

Procedure:
In a preferred embodiment, (RS)-N-benzyl-N-methyl-2-phenylglycinamide is treated with di(o-toluoyl)-L-tartaric acid in methanol at 20° C. The precipitated salt is filtered and washed with methanol, then dried providing (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 92.7% d.e. (chiral HPLC). This material is reslurried in hot methanol, filtered, washed and dried to providing (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 99% d.e. (37% overall yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: OCc1ccc(Br)cc1
Product: OCc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (2.0 g, 6 mmol) and commercially available 4-bromobenzyl alcohol (1.37 g, 7 mmol) according to general procedure II. Obtained as a light brown solid (575 mg, 22%). MS (ISP) 462.1 [(M+H)+]; mp 200–202° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[N:14]2[N:15]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]2[CH2:12][CH2:11]1)C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)(Cl)Cl.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[N:15][N:14]3[C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C:13]=23)=[CH:19][CH:20]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3COCc2ccccc2)n1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3CO)n1
Reaction time: 2 h

Procedure:
To a solution of (S)-6-benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.3 g, 0.73 mmol) in chloroform (1.0 mL) is added trimethylsilyl iodide (0.173 mL, 1.21 mmol). The mixture is stirred 2 h, diluted with methanol (10 mL), stirred 10 min, and concentrated in vacuo. The residue is taken up in ethyl acetate (50 mL), washed with aqueous sodium thiosulfate (2×50 mL), saturated sodium bicarbonate solution, and brine. The resulting solution is dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (3% methanol/ethyl acetate) to yield the title compound, 149 mg (64%), as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OC)C3)cc1

Procedure:
Method as example 34 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and methyl chloroformate as starting materials.
Reaction SMILES: O.[CH3:2][C@@H:3]1[C:11]2[C:6](=[CH:7][C:8](B3OCCNCCO3)=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Br[C:40]1[C:49]([O:50][CH:51]([F:53])[F:52])=[C:48]2[C:43]([C:44](=[O:62])[C:45]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:46][N:47]2[CH:54]2[CH2:56][CH2:55]2)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.C(O)(=O)C.COCCOCCOC>[CH:54]1([N:47]2[C:48]3[C:43](=[CH:42][CH:41]=[C:40]([C:8]4[CH:7]=[C:6]5[C:11](=[CH:10][CH:9]=4)[C@@H:3]([CH3:2])[N:4]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:5]5)[C:49]=3[O:50][CH:51]([F:53])[F:52])[C:44](=[O:62])[C:45]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:46]2)[CH2:56][CH2:55]1
Reactant: C[C@@H]1c2ccc(B3OCCNCCO3)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]4C)ccc2c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
In a mixed solvent of 50.6 ml of water and 50.6 ml of diethylene glycol dimethyl ether is suspended 13.5 g of 2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane and to this suspension is added 1.58 ml of acetic acid, after which the resulting mixture is stirred for 30 minutes. To this mixture are further added 10.1 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, 5.59 g of sodium carbonate and 0.088 g of bis(triphenylphosphine)palladium(II) chloride, and the resulting mixture is heated under reflux for 2 hours in a nitrogen atmosphere. The reaction mixture is cooled to 40° C. and thereafter the organic layer is separated. To the organic layer obtained is added 30 ml of ethanol and the crystals deposited are collected by filtration to obtain 17.3 g of ethyl 1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate. The physical property values of this compound were identical with those of the compound obtained in Production Example II-1.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH:37]([OH:47])[C:38]2[CH:39]=[CH:40][C:41]([OH:46])=[C:42]([CH2:44][OH:45])[CH:43]=2)=[CH:22][CH:23]=1>C(OCC)(=O)C>[CH:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH:37]([OH:47])[C:38]2[CH:39]=[CH:40][C:41]([OH:46])=[C:42]([CH2:44][OH:45])[CH:43]=2)=[CH:22][CH:23]=1.[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:11]=[CH:12][C:13]([O-:15])=[O:14])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Agent: OCc1cc(C(O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Solvent: CCOC(C)=O
Product: O=C([O-])C=Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.35 g (6 mmol) of 4-phenylcinnamic acid is dissolved by refluxing in 75 mL of ethyl acetate. To this solution is added a warm solution of 2.5 g (6 mmol) of salmeterol in 25 mL of ethyl acetate. The solution is allowed to cool and stirred for 16 hours at room temperature. The suspension is filtered, the precipitate is washed with ethyl acetate and tert-butylmethylether and dried in vacuo at 25° C.-30° C. 47 g of the title compound are obtained as a colorless solid. Melting point: 109° C. 2.2. Salmeterol-5-(2,4-difluorophenyl)salicylate Salt 2c
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([O:35]CC)=[O:34])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)c(F)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4cc(F)c(F)c(F)c4)CC3)c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A mixture of 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluoro-phenoxy)ethyl]piperidine-4-carboxylate in 50 cm3 of dioxane, 50 cm3 of methanol and 4.4 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 18 hours. A further 4.4 cm3 of aqueous 5N sodium hydroxide solution were added to the reaction mixture, which was stirred for 6 hours in the region of 70° C. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (1.1 kPa) at a temperature in the region of 50° C. The residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 4 cm; height 20 cm), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 60-cm3 fractions. Fractions 8 to 19 were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and oven-dried under reduced pressure (10 kPa) at about 50° C. 0.59 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at about 120° C.