Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]1[CH:12]2[CH:7]([O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11]2)[CH:6]([OH:17])[CH2:5][CH2:4]1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:17][CH:6]2[CH:7]3[O:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[O:11][CH:12]3[CH2:3][CH2:4][CH2:5]2)[CH2:23][CH2:24]1
Reactant: OC1CCCC2Oc3ccccc3OC12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)OC1CCCC(OCCN3CCOCC3)C1O2
Reaction time: 5 h

Procedure:
In a 10-liter reactor there were introduced 6 kg of 50% caustic soda solution, 1,150 g (5.576 moles) of the alcohol of Example 1, 986 g (5.3 moles) of 4-(2-chloroethyl)morpholine hydrochloride and 0.5 g of crown ether 18-crown-6 (1,4,7,10,13,16-hexaoxacycloocta-decane), and the mixture was then brought to 120° C. for 5 hours with stirring. After being cooled, the mixture was extracted with ether and the extract was washed with water dried over Na2SO4 and filtered, the solvent was evaporated and the product distilled under vacuum. There were thus obtained 1,330 g of the title-compound of boiling point 180° C. at a pressure of 65 Pa, having the elementary analysis:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:7][C:5]1([F:8])[CH2:4][C@H:3]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)[C@@H:2]([NH:1][C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][N:25]=2)[CH2:6]1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.15 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 29 mg, 0.16 mmol) and DIPEA (26 μl, 0.15 mmol) in dry DMSO (485 μl). The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.Cl.[CH3:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:7][C:4]1[S:3][C:2]([N:12]2[CH2:13][CH2:14][CH:10]([CH3:9])[CH2:11]2)=[N:6][CH:5]=1
Reactant: CC1CCNC1
Reactant: Brc1cnc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(c2ncc(Br)s2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2,5-Dibromothiazole (250 mg, 1.029 mmole), 3-methyl-pyrrolidine hydrochloride (188 mg, 1.544 mmole), and K2CO3 (569 mg, 4.12 mmole) were combined in DMF (5 mL) then heated to 100° C. After stirring overnight the mixture was cooled to RT, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (234 mg, 92%) as a pale yellow oil. 1H NMR (399 MHz, CDCl3): δ 7.06 (s, 1 H); 3.58-3.45 (m, 2 H); 3.45-3.35 (m, 1 II); 2.97 (dd, J=9.7, 7.7 Hz, 1 H); 2.47-2.36 (m, 1 H); 2.20-2.10 (m, 1 H); 1.73-1.63 (m, 1 H); 1.12 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]1([CH2:11][CH2:12][CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[C:5]1([CH2:11][CH2:12][CH:13]([OH:14])[CH:1]=[CH2:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C[Mg]Br
Reactant: O=CCCc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To vinyl magnesium bromide (550 ml of a 1.0M solution) was added 3-phenylpropionaldehyde (36.68 g, 0.273 mol) in tetrahydrofuran (300 ml) under argon at 0°. This mixture was stirred for one hour at room temperature, quenched with aqueous ammonium chloride and ice, and extracted into ethyl ether. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol which was carried on without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12.[CH3:32][S:33]SC.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:33][CH3:32])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc2N2C1=N[C@@H]1CCC[C@@H]12
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Temperature: 25 °C
Yield: 12.3 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.12 mmol) and methyl disulfide (21.3 μL, 0.24 mmol) are dissolved in 1 mL of anhydrous THF, and then 360 uL of 1.0 M LDA in THF is added dropwise. The reaction mixture is stirred at room temperature for an hour, and then quenched with saline. The mixture is separated with a semi-preparative HPLC to give 6.8 mg of pure product as pale yellow solids. MS (ESI) m/z 463.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)[O:18][C:13]=2[C:12]([F:30])=[CH:11][C:10]=1[F:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>O1CCCC1>[F:31][C:10]1[CH:11]=[C:12]([F:30])[C:13]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)=[CH:16][C:15](=[O:29])[C:14]=2[C:9]=1[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCBr)c(F)cc(F)c3o2)cc1F
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCN4CCCC4)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h

Procedure:
500 mg (1.01 mmol) of Compound 59 obtained in Example 59 was dissolved in 5 ml of tetrahydrofuran, 0.17 ml of pyrrolidine was added and the mixture was heated at reflux for 5.5 hours. At 1 hour and 1.7 hours after the reaction was started, each 0.17 ml of pyrrolidine was added. At 3.5 hours and 4.5 hours, each 0.17 ml of pyrrolidine was added. At 3.5 hours and 4.5 hours, each 0.08 ml of pyrrolidine was added. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine=90:10:1) and triturated with n-hexane to give Compound 63 which was converted into hydrochloride according to the same manner as that in Example 62 to give 465 mg (83%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=O)[CH2:5][CH2:6][C:7](O)=[O:8])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH3:2]
Reactant: CCCCCCCN(CC)C(=O)CCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCN(CC)CCCCO

Procedure:
In a manner similar to Preparation 5, react 4-[ethyl-(heptyl)amino]-4-oxobutyric acid with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([S:4][CH:5]([CH2:6][C:7]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:8])[CH:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:16])(=[O:3])[CH3:2]
Reactant: NCC(N)=O
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(N)=O)SC(C)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]-amino]carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N-ethyl-N1 -dimethylaminopropylcarbodiimide hydrochloride (116 mg, 0.6 mmol), 1-hydroxybenzotriazole (90 mg, 0.58 mmol), glycinamide hydrochloride (64 mg, 0.58 mmol) and diisopropylethylamine (0.2 ml, 1.14 mmol) in dichloromethane was stirred at 5° C. for 2 h then at room temperature overnight. The mixture was cooled in ice and the solid was collected by filtration and washed well with dichloromethane. The solid was triturated with 1 M citric acid, then filtered, washed with water and dried. Recrystallisation from methanol/ ether gave the title compound as a single isomer (Isomer A), 75 mg (30%) mp 218°-219° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[C:27]([CH:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)=[CH:32][CH:31]=2)[OH:29])=[CH:26][N:25]=[CH:24]1>C(Cl)Cl>[O:23]1[C:27]([C:28]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)=[CH:34][CH:35]=2)=[O:29])=[CH:26][N:25]=[CH:24]1
Reactant: OC(c1ccc(OC2CCCCO2)cc1)c1cnco1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Reaction time: 1 h
Yield: 42 %

Procedure:
Dess-Martin periodinane (25 g, 60 mmol) was added to a solution of 75.1 (17 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1:2 EtOAc/hexane) to obtain compound 75.2 (5.74 g, 21 mmol). MS ESI (pos.) m/e: 274.1 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[C:10](#[N:13])C=C>C(O)C>[CH3:6][C:8]1[CH:9]=[C:3]([CH:4]([CH3:5])[C:10]#[N:13])[S:2][CH:1]=1
Reactant: C=CC#N
Reactant: CSc1ccc(N)cc1
Solvent: CCO
Product: Cc1csc(C(C)C#N)c1

Procedure:
Dissolve 4-(methylmercapto)aniline (25.7 g, 0.185 mol) and acrylonitrile (11.7 g, 0.22 mol) in ethanol (700 mL) and heat at reflux for 18 hours. Evaporate the solvent in vacuo and purify by distillation to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.P(=O)(O)(O)O>CC(O)C.CCCCCC>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:33][CH:32]=1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)C(=O)CCC(=O)O)cc1

Procedure:
2-Ketoglutaric acid (98.5%, 1.484 g, 10.0 mmol) was suspended in 2-propanol (25 mL), cooled in ice and neutralized with a 40% aqueous solution of tetrabutylammonium hydroxide (5.9 mL, 9.0 mmol). The resulting solution was diluted with hexane (7 mL), dried in vacuo (below 30° C.), dissolved in a mixture of 2-propanol (15 mL) and hexane (5 mL) and dried as above to a viscous syrup (4.834 g). The residue was protected with argon, dissolved in N,N-dimethylacetamide (5 mL), and p-methoxybenzyl chloride (1.25 mL, 9.0 mmol) was added. The mixture was allowed to react at room temperature under argon protection for 65 h. An 0.8 M aqueous solution of phosphoric acid (40 mL) was added, the mixture was extracted with ethyl acetate, the organic layer was washed with 0.8 M phosphoric acid, with water, and dried. The crude monoester (2.266 g) was purified by flash chromatography (silica-gel, chloroform-ethyl acetate, 100:0 to 1:1, containing 0.2% of acetic acid) and crystallized from ethyl acetate-hexane. Yield of 3: 1.330 g (56%), 1H NMR (CDCl3) detected 60% of the open tautomer 3a and 40% of the cyclic tautomer 3b.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of 1-(2-chloropyrimidin-4-yl)ethanone (600 mg, 3.83 mmol) in MeOH (5 mL) at 0° C. was added sodium borohydride (145 mg, 3.83 mmol) and stirred for 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)ethanol (220 mg, 1.39 mmol, 36% yield). MS ESI: [M+H]+ m/z 159.0. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.1, 1H), 7.39 (d, J=5.1, 1H), 4.87 (q, J=6.6, 1H), 1.53 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CS(C)=O>[C:13]1([CH:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:19]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC(CCNCc1ccccc1F)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(C2CCNCc3ccccc3O2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 40.9 %

Procedure:
A mixture of N-(2-fluorophenylmethyl)-3-hydroxy-3-phenylpropylamine (4.5 g, 17 mM), 50% sodium hydride dispersion (870 mg, 17 mM) and dimethylsulphoxide (200 ml) was stirred for 24 hours at 50° C. under argon. The mixture was cooled to ambient temperature, poured onto water (700 ml) and extracted with ether (3×200 ml). The combined ether layers were extracted with 1 N hydrochloric acid (3×50 ml), the acid layer basified and extracted with ether (2×200 ml). The organic phase was dried and the solvent removed under reduced pressure. Recrystallisation from cyclohexane gave the title compound (1.7 g) m.p. 73°-4° C. Found: C, 80.1; H, 7.4; N, 5.9%; C16H17NO requires: C, 80.3; H, 7.2; N, 5.9%.
Reaction SMILES: [C:1](=[O:6])(OC)[O:2][CH3:3].[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]([Si](C)(C)C)[CH:17]=[CH:16][N:15]([Si](C)(C)C)[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:3][O:2][C:1]([N:15]1[CH:16]=[CH:17][CH2:18][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14]1)=[O:6]
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: COC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1C=CCC(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of dimethyl carbonate (0.05 mL, 0.6 mmol) in 2 mL of dry THF was slowly added 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine I (0.2 mL, 0.68 mmol). A solution of TBAF in THF (0.06 mL, 0.06 mmol) was then introduced dropwise and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ether (2 times), and the combined organic layers were washed with brine and dried over K2CO3. The solvent was removed under reduced pressure and the crude material was purified by RPLC hexanes) to afford 0.1374 g (91%) of 3-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II as a clear oil. IR (thin film, neat, NaCl): 2949, 2826, 2764, 1721, 1695, 1437, 1334, 1313, 1194, 983 cm−1. 1 HNMR (300 MHz, CDCl3): δ 6.68-6.51 (m, 2 H), 4.88-4.77 (m, 1 H), 3.65 (s, 3 H), 2.95-2.91 (m, 1 H), 2.64-2.62 (m, 2 H), 2.41-2.33 (m, 1 H), 2.05-1.93 (m, 5 H), 1.68-1.53 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 151.81, 123.15, 122.74, 120.28, 119.63, 118.08, 117.71, 106.22, 105.94, 70.37, 56.60, 53.05, 40.16, 40.08, 28.76, 28.38, 22.37, 21.56, 21.05. HRMS Calcd for C12H18N2O2: 223.1447 [M+H]+. Found: 223.1434 [M+H]+. [α]24D−65.5 (c =8, CH2Cl2).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:23])[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]([S:18](Cl)(=[O:20])=[O:19])=[C:10]([CH3:22])[CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:23])[C:13]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:12][C:11]([S:18]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[C:10]([CH3:22])[CH:9]=1
Reactant: OC1CCCCC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)OC2CCCCC2)cc1S(=O)(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask, equipped with stirrer, condenser and thermometer, 100.0 parts of pyridine and 16.55 parts of cyclohexanol were mixed under a nitrogen atmosphere and chilled to 0° C. with an ice water bath. To this solution 25.0 parts of 1,3-xylene-4,6-disulfonyl dichloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 300 parts of methylene chloride. The organic layer was washed successively with cold 6N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 300 part-portions), and water (twice with 300 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the dicyclohexyl 1,3-xylene-4,6-disulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Product: O=C(Nc1cccc(F)c1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-amino-6-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.1 (M−H−, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:28])[NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:28][C:20]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Reactant: NC(=C[N+](=O)[O-])NC1CCCCC1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 37 grams of 2-nitro-N-cyclohexyl-1,1-ethenediamine at 80° C. for 3 hours. Th mixture is cooled and the procedure described in Example 1 is followed. The product melts at 97°-99° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:38])[NH:15][C@H:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]1[NH:31][C:30]2[CH:32]=[C:33]([C:36]#[CH:37])[CH:34]=[CH:35][C:29]=2[N:28]=1)=[O:21])[CH:17]([CH3:19])[CH3:18].[CH3:39][O:40][C:41](=[O:66])[NH:42][C@H:43]([C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54]1[NH:58][C:57]2[CH:59]=[C:60]([N:63]=[N+:64]=[N-:65])[CH:61]=[CH:62][C:56]=2[N:55]=1)=[O:48])[CH:44]([CH3:46])[CH3:45]>C1(C)C=CC=CC=1.[Cu]I>[CH3:12][O:13][C:14](=[O:38])[NH:15][C@H:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]1[NH:31][C:30]2[CH:32]=[C:33]([C:36]3[N:65]=[N:64][N:63]([C:60]4[CH:61]=[CH:62][C:56]5[N:55]=[C:54]([C@@H:50]6[CH2:51][CH2:52][CH2:53][N:49]6[C:47](=[O:48])[C@@H:43]([NH:42][C:41]([O:40][CH3:39])=[O:66])[CH:44]([CH3:46])[CH3:45])[NH:58][C:57]=5[CH:59]=4)[CH:37]=3)[CH:34]=[CH:35][C:29]=2[N:28]=1)=[O:21])[CH:17]([CH3:19])[CH3:18]
Reactant: C#Cc1ccc2nc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c2c1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(N=[N+]=[N-])cc2[nH]1)C(C)C
Agent: [Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3cn(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)nn3)cc2[nH]1)C(C)C
Reaction time: 0.5 h

Procedure:
DBU (154 μL, 1.03 mmol) is diluted in 0.5 mL of anhydrous toluene. Copper(I) iodide (5.9 mg, 0.031 mmol) is added followed by a solution of {(S)-1-[(S)-2-(6-Ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester intermediate 14 (38 mg, 0.10 mmol) in 0.5 mL of toluene and a solution of {(S)-1-[(S)-2-(6-Azido-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester intermediate 20 (50 mg, 0.13 mmol) in 1.0 mL of toluene. The resulting mixture is submitted to microwave for 30 minutes at normal power. The final mixture is filtrated through a pad of celite using DCM. The filtrate is concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 0% to 15%) The compound is further purified by reverse phase HPLC to give title compound (6.5 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[C:28]1([C:34]2[CH:35]=[CH:36][C:37]([CH2:40]Br)=[N:38][CH:39]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:40][C:37]4[CH:36]=[CH:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:39][N:38]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2)cn1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3ccc(-c4ccccc4)cn3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (180 mg) (Preparation 1), 5-phenyl-2-picolyl bromide (138 mg), K2CO3 (84 mg) and Cs2CO3 (30 mg) in DMF (5 mL) wase stirred at r.t. under nitrogen for 48 hours. The mixture was poured onto 1N HCL, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated to dryness. The residue was purified by column chromatography (hexane/EtOAc 5:1 then 1:1) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:11]2[N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([Cl:20])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:21][NH2:22]>O1CCCC1>[Cl:20][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([NH:22][CH3:21])[N:11]3[N:12]=[C:13]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:10]3[C:9]=2[CH:8]=1
Reactant: Clc1ccc2nc(Cl)n3nc(-c4ccco4)nc3c2c1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12

Procedure:
To a solution of 1.45 g of 5,9-dichloro-2(2-furyl)[1,2,4]triazolo[1,5-c]quinazoline in dry tetrahydrofuran (150 cc) at 50° is added gaseous methylamine over 40 minutes. The mixture is concentrated to dryness, triturated with water and filtered to afford a white solid. This is recrystallized by dissolution in hot toluene and, after several minutes of heating to remove water by azeotropic distillation, addition of cyclohexane during cooling. Pure 9-Chloro-2-(2-furyl)-5-methylamino[1,2,4]triazolo[1,5-c]quinazoline, mp 166°-168°, is thus obtained.