Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6](=[CH:7][Br:8])[O:5][C:4](=[O:9])[C:3]=1[CH:10]([OH:14])[CH2:11][CH2:12][CH3:13].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[C:6](=[CH:7][Br:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(O)C1=C(Br)C(=CBr)OC1=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)C1=C(Br)C(=CBr)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 4-bromo-5-(bromomethylene)-3-(1-hydroxybutyl)-2(5H)-furanone (2.77 g, 8.5 mmol) in acetone (75 ml) was added dropwise with stirring Jones reagent (12 ml, prepared by dissolving chromium trioxide (13.36 g) in sulfuric acid (11.2 ml) and water (38.5 ml). The mixture was stirred at room temperature for 1 h and the progress of the reaction monitored by thin layer chromatography. After the completion of the reaction, the mixture was poured into water (200 ml) and extracted with ether (3×100 ml). The combined ether extracts were washed with brine (100 ml), dried over sodium sulfate and evaporated to yield the crude ketone (2.23 g, 81%) as a yellow solid. Recrystallisation of the crude ketone from dichloromethane/hexane gave the pure ketone as yellow plates, m.p. 83–84° C. νmax 1700, 1680, 1630, 1540, 1310, 1000 cm−1. 1H n.m.r. δ (CDCl3) 0.97, t, J 7.2 Hz, (H4′)3; 1.70, m, (H3′)2; 2.93, t, J 7.2 Hz, (H2′)2; 6.74, s, 5-CHBr. 13C n.m.r. δ (CDCl3): 13.6, C4′; 16.7, C3′; 44.4, C2′; 99.3, 5-CHBr; 125.7, C4; 138.1, C3; 150.4, C5; 163.5, CO; 194.1, C1′. Mass spectrum: m/z 326, (M (81Br2), <5%); 324 (M (81Br, 79Br), 5); 320, (M (79Br2), <5); 298 (10); 296 (22); 281 (16); 279 (8): 225 (4); 131 (14); 77 (32); 71 (52), 43 (100).
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: ClCCN1CCOCC1
Reactant: OC1CCCC2Oc3ccccc3OC12
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: [C:1]([C:4]1[C:9]([CH3:10])=[C:8]([Cl:11])[C:7]([CH3:12])=[CH:6][N:5]=1)(O)=[O:2].B.C1COCC1.C1COCC1.O.[Cl-].[Na+]>CN(C)C=O>[Cl:11][C:8]1[C:7]([CH3:12])=[CH:6][N:5]=[C:4]([CH2:1][OH:2])[C:9]=1[CH3:10]
Reactant: Cc1cnc(C(=O)O)c(C)c1Cl
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(CO)c(C)c1Cl
Reaction time: 1.5 h
Yield: 51 %

Procedure:
2-carboxy-4-chloro-3,5-lutidine (1 eq.) was suspended in dry dimethylformamide and BH3.THF solution (1M in tetrahydrofuran, 3.5 eq.) was added. The mixture was heated to 60ℑ C. and stirred under a nitrogen atmosphere until completion (1.5 hours). The mixture was cooled in an ice bath and THF/H2O (1:1) mixture (10 volumes) was added slowly. The aqueous layer was saturated with sodium chloride and the tetrahydrofuran layer was separated. The aqueous layer was extracted with ether. The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The 4-Chloro-2-hydroxymethyl-3,5-Lutidine product was obtained in 51% yield.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Fe]>[C:9]([C:2]1[CH:3]=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:1]=1[O:7][CH3:8])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: [Fe]
Product: COc1ccc(C(=O)c2ccccc2)cc1C(=O)c1ccccc1

Procedure:
Direct reaction of anisole, which is highly activated, with benzoyl chloride in the presence of iron powder to give 2,4-dibenzoylanisole is described in Zh. Org. Khim. 6 (1970) 535.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:17][N:16]=1
Reactant: O=C(c1ccc[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1c[nH]c(-c2n[nH]c3ncccc23)c1
Yield: 81 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (1 g, 4.8 mmol) and hydrazine hydrate (0.5 mL) in ethanol (15 mL) was heated to reflux for overnight. The reaction was concentrated and the residue was triturated with dichloromethane (to remove any unreacted starting material. The solid was filtered, washed wit water and dried to give 720 mg (81%) of the titled compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[C:3]([OH:12])[C:2]=2[Cl:1])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: BrCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Combine 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (6.00 g, 32.2 mmol) and 1,4-bis-bromomethyl-benzene (8.48 g, 31.2 mmol) and potassium carbonate (4.44 g, 32.2 mmol) in acetone (400 ml) and heat to reflux. After 1 h, cool to room temperature and add 10% hydrochloric acid (300 mL). Filter to collect and triturate resultant solid in 1:1 ether/hexanes. Purify by column chromatography, eluting with 40% tetrahydrofuran/hexanes to obtain 1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone (3.00 g, 8.12 mmol) as a white solid. MS (m/z): 368.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH3:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][CH2:40][C:15](=[O:16])[C@@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
The title compound was prepared according to EXAMPLE 229 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid (EXAMPLE 228) and 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (Preparation 86). Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=558.48 [M+H]+; RT=3.82 min.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].CS(O[C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][Si](C(C)(C)C)(C)C)=[CH:23][C:22]=2[O:35][Si](C(C)(C)C)(C)C)[CH2:17][CH2:16]1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]1([S:7][C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[OH:35])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Oc1ccc([C@H]2CC[C@H](Sc3ccccc3)CC2)c(O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A round bottom flask containing thiophenol (30 μl, 0.29 mmol), cesium fluoride (44 mg, 0.29 mmol) and N,N-dimethylformamide (3 ml) was warmed at 40° C. for 1 hr. To this was added cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl methanesulfonate (100 mg, 0.19 mmol) in N,N-dimethylformamide (1 ml) and the reaction mixture stirred at 50° C. for 18 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/petrol, 1:3) afforded the title compound (23 mg, 40%) as an off-white solid. δH (d4-MeOH) 1.40-1.57 (4H, m), 1.82-1.90 (2H, m), 2.04-2.16 (2H, m), 2.80 (1H, m), 3.13 (1H, m), 6.19-6.28 (2H, m), 6.88 (1H, d), 7.23 (1H, m), 7.30 (2H, m), 7.40 (2H, m); m/z (ES+) 301 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][N:55]=2)[OH:53])=[CH:48][CH:47]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([CH:52]([OH:53])[C:54]5[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][N:55]=5)=[CH:48][CH:47]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Cc1ccc(C(O)c2ccc(N)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(C)cn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 72 h
Yield: 75.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g), 1-hydroxybenzotriazole (0.28 g), (4-aminophenyl)(5-methylpyridin-2-yl)methanol (0.29 g) and triethylamine (0.60 ml) in DMF (10 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and 4-dimethylaminopyridine (1 flake) at room temperature and the mixture was stirred for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1) and further recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 103) (529.9 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)CBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.1 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.28 g, 1.45 mmol), acetonitrile (15 mL), potassium carbonate (0.4 g, 2.9 mmol) and 1-bromo-2-methylpropane (0.15 mL, 1.59 mmol) was stirred at ambient temperature for 5 h and then at 60° C. for 2 h. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1) gave the title compound (0.193 g). [α]D=−22.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 162-163° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 2), 212 (bp), 182 (46), 213 (13), 57 (10), 127 (10).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:12]([CH3:11])(=[O:16])[O:13][CH2:14][CH3:15]
Reactant: CCOP(C)OCC
Reactant: BrCc1cccc(CBr)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(C)(=O)Cc1cccc(CBr)c1
Temperature: 150 °C
Yield: 44 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (7.75 g, 29.38 mmol) in DMF (10 mL) was added diethyl methylphosphonite (2.0 g, 14.69 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with ethyl acetate (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 20-100% ethyl acetate in hexanes to give 1.89 g mg (44%) 65 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H), 1.33 (d, 3H), 3.08 (d, 2H), 3.97 (dt, 2H), 4.44 (s, 2H), 7.25 (m, 4H). LCMS: m/z for C11H16BrO2P++H observed 291.0 and 293.0 at 2.09 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:18][C:19]1[C:24]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32](=[O:34])[NH2:33])=[CH:29][CH:28]=[C:27]([C:35]([OH:37])=O)[CH:26]=2)=[O:21]>CN(C)C=O>[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32]([NH2:33])=[O:34])=[CH:29][CH:28]=[C:27]([C:35]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:37])[CH:26]=2)=[O:21]
Reactant: NC(=O)Nc1[nH]c2cc(C(=O)O)ccc2c1C(N)=O
Reactant: NCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(C(=O)NCCc3ccccc3)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
N,N-Diisopropylethylamine (0.20 mL, 1.14 mmol) and 2-phenethylamine (48 μL, 0.38 mmol) were added to a solution of 2-aminocarbonylamino-3-carbamoylindole-6-carboxylic acid (Compound 18-1, 0.10 g, 0.38 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate g, 0.38 mmol) in anhydrous N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with saturated sodium hydrogen carbonate aqueous solution (20 mL), water (20 mL), and dried under reduced pressure to give the title compound (0.11 g) as a slightly yellow solid (yield 77%).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:57])[CH2:56][CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][CH2:56][C:52]([F:57])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: FC1(F)CCNC1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as colorless gum (13.3 mg, 69%). MS(m/e): 407.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 99.3 %

Procedure:
Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl3 (100 mL) was added triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5 g, 52 mmol). The mixture was stirred at RT for 3d before concentrating and redissolving in EtOAc. The solution was washed sequentially with 10% aq. citric acid, water, and brine before drying over MgSO4 and concentrating under reduced pressure to give 2 (20 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1]I.[Mg].[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=[CH:15][N+:16]([O-:18])=[O:17].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:1])[CH2:15][N+:16]([O-:18])=[O:17]
Reactant: CI
Reactant: O=[N+]([O-])C=Cc1c[nH]c2ccc(Br)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C[N+](=O)[O-])c1c[nH]c2ccc(Br)cc12
Reaction time: 12 h
Yield: 49.5 %

Procedure:
Methyl iodide (35.5 g) was added to a stirred suspension of magnesium (4.8 g) in dry ether (100 ml) over a period of 10 min. To the grey solution was added a solution of 5-bromo-3-(2-nitroethenyl)-1H-indole (13.4 g) in dry tetrahydrofuran (250 ml) over a period of 11/2 h. The resulting mass was stirred vigorously for 12 h, followed by the careful addition of saturated ammonium chloride (250 ml). After separation of the organic phase, the aqueous phase was extracted with ether (500 ml). The combined organic extracts were successively washed with 5% sodium sulphite solution (500 ml) and water (500 ml). Evaporation of the dried (MgSO4) ethereal phase gave a brown oil which was chromatographed on Kieselgel 60 using diethyl ether as eluant to give the title compound as a yellow gum (7.03 g) T.L.C. silica/diethyl ether Rf 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[NH2:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24].[BH3-]C#N.[Na+]>C(O)C>[CH2:14]([O:13][C:11]([CH:10]([NH:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12])[CH3:15]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
A solution of ethyl 4-p-chlorophenyl-2-oxobutyrate (prepared from the acid by esterification with ethanol in refluxing CCl4) and L-alanyl-L-proline in ethanol can be treated with excess NaBH3CN and stirred at room temperature until reaction is complete. The ethanol can then be removed under vacuum and the product absorbed on strong acid ion-exchange resin. By elution with 2% pyridine in water, one can obtain N-(1-ethoxycarbonyl-3-p-chlorophenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]2([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19]2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]4([CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NC3(Cc4ccccc4)CC3)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(NC2(Cc3ccccc3)CC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(2-amino-6-{[1-(phenylmethyl)cyclopropyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (124 mg, 0.34 mmol) and hydrazine hydrate (99%, 2 mL) in ethanol (10 mL) was stirred and heated at 120° C. for 1 hour in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting solids were purified by reverse phase chromatography with CH3CN in water (0.08% ammonium hydrogen carbonate) (gradient: 35% to 45% in 6 min: flowrate: 30 mL/min), to afford the title compound (30 mg) as a white solid. LC-MS (ES) m/z=372 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.78 (d, 4H), 2.93 (s, 2H), 5.37 (s, 2H), 5.97 (s, 2H), 6.32 (s, 1H), 6.90 (s, 1H), 7.18 (d, 3H), 7.27 (t, 2H), 7.40 (s, 1H), 7.69 (d, 1H), 7.81 (s, 1H), 11.50 (s, 1H).