Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[CH:3]=[CH:2]1.I[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc4cc[nH]c4c3)c21
Temperature: 90 °C
Yield: 61.9 %

Procedure:
A solution of 6-indoleboronic acid (36 mg, 0.22 mmol) (from Step A above), (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one (54 mg, 0.15 mmol) (Starting Material 3) and sodium carbonate (52 mg, 0.49 mmol) in 5 mL DME and 2.5 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (10 mol %) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting product, (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one), was purified via flash column chromatography (40% EtOAc/hex) to yield 33 mg (62%) orange powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[C:15]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:17]1([CH2:16][C:15]2[C:10]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OB(O)c1cccs1
Reactant: Brc1ncccc1Cn1ccnc1
Product: c1csc(-c2ncccc2Cn2ccnc2)c1

Procedure:
Synthesized using 2-thiophenylboronic acid (161 mg, 1.26 mmol) and 5 (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 111 mg, 0.46 mmol, 73%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.39 (s, 2H), 6.88 (t, J=1.3 Hz, 1H), 7.13-7.15 (m, 2H), 7.17 (dd, J=7.9, 1.9 Hz, 1H), 7.20 (dd, J=7.9, 4.4 Hz, 1H), 7.23 (dd, J=3.8, 1.3 Hz, 1H), 7.50 (dd, J=5.0, 1.3 Hz, 1H), 7.51 (brs, 1H). 8.60 (dd, J=4.4, 1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.4, 119.3, 122.5, 127.2, 127.8, 128.5, 128.6, 130.3, 136.1, 137.5, 142.7, 149.0, 150.8; MS (ESI): m/z=241.79 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:12][N:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]([CH2:17][OH:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C1CCCCC1>[CH2:23]([O:18][CH2:17][CH:10]1[CH2:9][CH2:8][CH:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][N:11]1[S:13]([CH3:16])(=[O:15])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OCC1CCC(CO)N(S(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OCC1CCC(COCc2ccccc2)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(6-ring): To a solution of (2RS,5RS)-(5-tert-butoxymethyl-1-methanesulfonyl -piperidin-2-yl)-methanol (2.80 g) in dichloromethane (20 ml) and cyclohexane (30 ml) was added benzyl 2,2,2-trichloroacetimidate (3.03 g) and trifluoromethanesulphonic acid (0.2 ml). The reaction mixture was stirred 1 h at room temperature, poured onto a saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as eluents to obtain (2RS,5RS)-2-benzyloxymethyl-5-tert-butoxymethyl-1-methanesulfonyl-piperidine (3,6 g) as a syrup, MS: 369 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22])(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cccc(CN)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CC(=O)Nc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-(3-Acetylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminomethylphenyl)acetamide using method H. NMR; δH [2H6]—DMSO 9.92,(1H, s), 9.15,(1H, t), 8.01,(2H, d), 7.89,(1H, dd), 7.77,(1H, d), 7.52,(5H, m), 7.23,(1H, t), 6.99,(1H, d), 4.47,(2H, d), 2.56,(3H, s), 2.32,(3H, s), 2.01,(3H, s). LCMS; retention time 2.95 min, MH+ 441.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[N:19]1([NH2:24])[CH:23]=[CH:22][CH:21]=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:24][N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: Fc1ccccc1Cn1cnc2c(Cl)ncnc21
Reactant: Nn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccccc1Cn1cnc2c(Nn3cccc3)ncnc21
Yield: 91.2 %

Procedure:
A solution of 6-chloro-9-(2-fluorobenzyl)-9H-purine (4.2 g, 16 mmole) and 1H-pyrrol-1-amine (3 g, 36 mmole) in 25 ml isopropanol was stirred at reflux for thirty minutes then was cooled, diluted with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride, was dried (anhydrous MgSO4), filtered and evaporated to 6 g of a solid. The solid was purified by flash chromatography (silica, 15% ethyl acetate in dichloromethane) to give 4.5 g of 9-(2-fluorobenzyl)-N-(1H-pyrrol-1-yl)-9H-purin-6-amine, m.p. 204°-206° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22]#[N:23]>ClCCCl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([C:20]1[N:16]([CH3:15])[C:17]([CH2:21][C:22]#[N:23])=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1cccc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added dropwise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hyrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting residue is triturated with cold methanol to yield a precipitate of the desired product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo, and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. The desired product is isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 122-127° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>O1CCCC1>[CH2:25]([NH:27][C:28]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Reaction time: 0.25 h
Yield: 11.4 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (156 mg, 0.617 mmol) and triethylamine (86.1 mL, 0.617 mmol) were dissolved in tetrahydrofuran (6.2 mL), ethyl isocyanate (58.6 μL, 0.741 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (20.2 mg, yield 11%).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[H-].[Na+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:28]([O:4][C@@H:3]1[C@@H:5]([O:6][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:7]([O:8][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:9]([CH2:11][O:12][CH2:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)[O:10][C@H:2]1[S:1][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S[C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 177.6 %

Procedure:
p-Methylphenyl 1-thio-β-D-galactopyranoside (1.0 g, 3.5 mmol) was dissolved in dry DMF (15 mL) and cooled to −10° C. At this temperature (840 mg, 35 mmol) NaH was added and the mixture allowed to warm up to rt. and stirred for an additional 10 min. Then BnBr (4.1 mL, 35 mmol) was added, and the mixture was stirred for 5 h. At 0° C. 10 mL H2O was added and the mixture extracted with EtOAc (3×50 mL). The organic layer was dried over MgSO4 and evaporated to dryness. Flash chromatography using Hexane/EtOAc (5:1) gave the title compound as a white solid (2.01 g, 89%). [α]D22 −1.2° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3), δ 2.27 (s, 3H), 3.56-3.65 (m, 4H), 3.89 (t, 1H, J=9.4 Hz) 3.97 (s, 1H), 4.42 (ABq, 2H, J=11.6 Hz), 4.59-4.60 (m, 3H), 4.70 (m, 3H), 4.73 (ABq, 2H, J=10.1 Hz), 4.95 (d, 1H, J=11.5 Hz), 6.98 (d, 2H, J=8.6 Hz), 7.25-7.47 (m, 22H); 13C-NMR (400 MHz, CDCl3), δ 21.04, 68.68, 72.63, 73.48, 74.34, 75.54, 77.16, 77.24, 84.13, 87.95, 127.36, 127.49, 127.60, 127.65, 127.71, 127.78, 127.86, 128.09, 128.26, 128.35, 129.49, 132.10; HRMS (M+Cs) calcd for C41H42O5SCs 779.1807, found 779.1782.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[NH:10][C:11](=[O:19])[NH:12][C:13]=1OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[OH-].[Na+]>CO.[Pd]>[CH2:1]([C:8]1[C:9](=[O:20])[NH:10][C:11](=[O:19])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1[nH]c(=O)[nH]c(=O)c1Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1[nH]cc(Cc2ccccc2)c(=O)[nH]1
Yield: 79.8 %

Procedure:
A solution of 5-benzyl-6-methanesulphonyloxy-2,4-(1H,3H)-pyrimidinedione (3 g) and Et3N (2.1 ml) in MeOH was hydrogenated in the presence of Pd/C 5% (0.3 g) for 3 hr at 35° C. NaOH 5% (2.5 eq) was added and the catalyst filtered off. The solution was acidified to pH 2 with HCl 10%. The precipitated white solid was then collected by filtration, washed with water, ether and dried under vacuum to yield the desired 5-benzyl-2,4-(1H,3H)-pyrimidinedione: 1.635 g, 79.8% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[O:4][C:5](=[O:7])[CH:6]=1.[CH3:9][NH:10][NH2:11]>CC(O)=O>[Br:1][C:2]1[C:3](=[O:4])[NH:11][N:10]([CH3:9])[C:5](=[O:7])[CH:6]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1[nH]c(=O)c(Br)cc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromofuran-2,5-dione (100 g, 0.565 mol) in HOAc (1.0 L) cooled in an ice-water bath, 40% aq. methylhydrazine solution (65 g, 0.565 mol) was added dropwise while the internal temperature was held below 20° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried in vacuo to give desired product as a white solid: LC/MS m/z=206.9 (M+H)+; 1H NMR (400 MHz, CD3OD) δ: 7.35 (s, 1 H), 3.60 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:38])=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)c1
Reaction time: 8 h

Procedure:
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (1 mL) and diisopropylethylamine (0.5 mL) was added. To this solution m-anisoyl chloride (50 μL, 0.35 mmol) was added. The mixture was shaken overnight and evaporated to afford the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].Cl.[CH3:10]O>>[CH3:10][O:7][C:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8]
Reactant: O=C(O)C1CCCO1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydrofuran-2-carboxylic acid (37.7 g, 325 mmol) in methanol containing hydrogen chloride (200 mL) was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was taken up in dichloromethane (150 mL). The solution was washed with sodium hydrogen carbonate solution and water (in each case 2×100 mL), dried over sodium sulphate, filtered and concentrated to dryness.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([C:53]([F:55])([F:56])[F:54])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(C(F)(F)F)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-(trifluoromethyl)benzene and isolated as white solid. MS (m/e): 509.3 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-cyanobenzyl bromide
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:32]=[CH:31]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][CH2:44][N:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[N:34]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-quinoline
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(C2(O)c3ccccc3Sc3ccccc32)cc1
Product: Cc1ccc(C2(OC[C@H](N)C(=O)O)c3ccccc3Sc3ccccc32)cc1

Procedure:
from 9-(4-methylphenyl)-9H-thioxanthen-9-ol (Example 1p) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](O[C@H](C2C=CC=CC=2)C)=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH3:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:42][CH:43]=1>>[CH3:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([NH:47][C:34]([C:31]2([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[C:6]=5[NH:7][C:8]([NH:47][S:44]([C:41]5[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=5)(=[O:45])=[O:46])=[O:9])=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)[CH2:32][CH2:33]2)=[O:35])(=[O:46])=[O:45])=[CH:42][CH:43]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)c5ccc(C)cc5)CC4)cc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 315 using 1-{4′-[3-Methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and p-toluenesulfonamide.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (50 mg, 0.05 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-N6,N6-bis(2-hydroxyethyl)-3-methoxy- (47 mg, 0.08 mmol) in MeOH (3 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction mixture was stirred under a balloon of hydrogen overnight. Additional 10% palladium on carbon (30 mg, 0.03 mmol) was added and the reaction mixture was once again vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction was stirred under a balloon of hydrogen overnight, filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N11-[(dimethylamino)sulfonyl]-6,7-dihydro-N6,N6-bis(2-hydroxyethyl)-3-methoxy- (39 mg, 0.06 mmol, 83%) as a yellow solid. Mixture of atrope diasteromers: 1HNMR (300 MHz, CD3OD) δ 8.13-7.93 (m, 1H), 7.88-7.79 (m, 1H), 7.66-7.58 (m, 1H), 7.40-7.31 (m, 1H), 7.06-6.88 (m, 2H), 4.56-4.34 (m, 2H), 3.94-3.86 (m, 3H), 3.85-3.64 (m, 8H), 3.48-3.37 (m, 1H), 3.03-2.82 (m, 2H), 2.99 (s, 6H), 2.77-2.63 (m, 1H), 2.19-1.17 (m, 10H). LCMS: m/e 625 (M−H)−, ret time 2.44 min, column A, 4 minute gradient.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1)=[O:5])[CH3:2].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
Alkylation of tert-butyl (3 RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyinaphthalene analogously to the procedure described in Example 22(i) gave tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 516 (M+H)+.