Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[CH3:23][S:24]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:26])=[O:25]
Reactant: OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
A mixture of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propane-1,2-diol (100 mg, 0.31 mmol) and TEA (94 mg, 0.93 mmol) in THF (6 mL) was stirred under N2 at 0° C., MsCl (36 mg, 0.31 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and RT overnight. Water was added and after extraction with EA, the organic layer was washed with water, brine, dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatography (PE:EA=2:1˜1:1) to give the product of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)-2-hydroxypropyl methanesulfonate (60 mg, yield: 48%). 1H-NMR (MeOD, 400 MHz) δ 7.80 (d, J=7.6 Hz, 1H), 7.26˜7.32 (m, 2H), 7.09˜7.11 (m, 1H), 7.04 (s, 1H), 6.70 (t, J=7.6 Hz, 1H), 4.20˜4.29 (m, 3H), 3.09˜3.13 (m, 5H). MS (M+H)+: 399/401.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)nc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.830 g, 6.3 mmol) and the mixture stirred at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.923 g, 6.3 mmol) was added dropwise and the mixture was stirred at 0° C. for about 1 hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 25-30% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH:30]([CH:38](O)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:9][CH:38]([CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:45][CH:46]=1)[CH:30]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:29][CH2:28][NH:27][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(O)CCc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
Benzoic acid (48.5 mg), 4-dimethylaminopyridine (24.3 mg) and triethylamine (0.08 ml) were added to a solution of tert-butyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-biphenyl-4-yl-3-hydroxypentanoate (200 mg) in dichloromethane (5 ml) at 0° C. and the reaction mixture was stirred for 15 minutes. 1-Ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (152 mg) was added and the reaction mixture was stirred overnight. The reaction mixture was taken in distill water and extracted with dichloromethane (20 ml). The organic layer was washed with dilute sodium bicarbonate solution, brine solution, dried over anhydrous sodium sulphate and evaporated under vacuum. The residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane as eluent to furnish the title compound (180 mg).
Reaction SMILES: CC1C=CC(S(N[C@H](CC#C)C)(=O)=O)=CC=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]#[C:27][Si](C)(C)C)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@H:24]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]#[CH:27])=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Agent: C#CC[C@H](C)NS(=O)(=O)c1ccc(C)cc1
Product: C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1

Procedure:
Proceeding as described for (54), but using (R)—N-(1-(4-fluorophenyl)-4-(trimethyl-silyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamide afforded (R)—N-(1-(4-fluoro-phenyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamide (56). MS (m/z): 372.1 (M+H) (Calc'd for C17H13F4NO2S: 371.35).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Mg]Cl)(C)C.[CH:24](=[O:27])[CH2:25][CH3:26].[NH4+].[Cl-]>C1COCC1>[OH:27][CH:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH2:25][CH3:26]
Reactant: CCC=O
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
124-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.2 g, 6.21 mmol) in dry THF (150 mL) was cooled to −78° C. under Ar, and a 2M solution of iPrMgCl in THF (18.6 mL, 37.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and propionaldehyde (3.61 g, 62.1 mmol) was then added. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT overnight. The reaction mixture was poured onto a saturated aq. solution of NH4Cl and extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, heptane to AcOEt/MeOH 9:1) to give the title compound (231 mg). UPLC-MS: MS 287.2 (M+H+); UPLC rt 0.59 min.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][CH2:9][NH:10][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(F)c1O
Reactant: CC(=O)OC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NCCc1cccc(F)c1O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.54 g of (3-fluoro-2-hydroxyphenyl)acetonitrile, 1.87 ml of acetic anhydride and 2.41 g of nickel chloride hexahydrate in 75 ml of methanol is admixed at 0° C. with 2.72 g of sodium borohydride in portions and stirred at room temperature over 22 hours. The reaction mixture is concentrated by evaporation, and the residue is diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution and clarified by filtration. The aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (95:5 dichloromethane-methanol); Rt=2.60.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[C:12]1([CH:18]2[NH:22][C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>CCOCC.O>[C:12]1([CH:18]2[N:22]([C:27]([O:29][CH3:30])=[O:28])[C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)Cl
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2)N1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)N1C(c2ccccc2)SC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a mixture of 60 g. of sodium carbonate in 330 ml. of water and 220 ml. of 10% sodium bicarbonate was added 62.7 g. (0.3 mole) of 2-phenyl-4-(R)-carboxythiazolidine. A solution of 23.0 ml. (28.4 g., .3 mole) of methyl chloroformate in 75 ml. of ether was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for one additional hour. The entire reaction mixture, including some solid which occasionally separated, was acidified carefully (foaming) to pH 1 by the dropwise addition of about 50 ml. of 6N HCl. The reaction was extracted 3 × 300 ml. portions of methylene chloride. The organic phases were dried over sodium sulfate and evaporated to afford 77.4 g (97%) of the 2-phenyl-3-carbomethoxy-4-(R)-carboxythiazolidine as a white crystalline solid, having a m.p. of 129°-130° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH3:16])[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[N:20][CH:21]=1)[CH3:27]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)nc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 300 mg (1.316 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-chroman (Compound 48) and 245.6 mg (1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml of triethylamine was placed in a pressure tube and a stream of nitrogen was bubbled through the solution for 15 min. The tube was then flushed with argon and a finely ground mixture of 100 mg (0.1425 mmol) of bis (triphenylphosphine) palladium (II) chloride and 50 mg (0.2625 mmol) of cuprous iodide was added to the solution. The pressure tube was then sealed and the reaction mixture heated at 60 degrees C. for 72 h. The mixture was cooled to room temperature and the triethylamine removed under vacuum. The residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDC13): & 1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J~7.2 Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J~7.2 Hz), 6.70 (1H, s), 7.55-761 (2H, m), 8.28 (1H, dd, J~8.2 Hz, 2.1 Hz), 9.22 (1H, d, J~2.1 Hz). MS exact mass, m/e 377.1982 (calcd. for C24H27O3N, 377.1991).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH2:19])[C:6]=2[CH:20]=1.O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][C:22](=[O:24])[CH3:23])[C:6]=2[CH:20]=1
Reactant: NCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCCCC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
3-Chloro-5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution heated to refluxing for 20 minutes. The solution then is cooled and poured into a large volume of water. The mixture is stirred until the excess reagent is hydrolyzed. The product then is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (130 mg) in acetonitrile (4 ml) was added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:25]([O:28][C@@H:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C@H:31]([NH2:40])[CH2:30]1)[CH:26]=[CH2:27].[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>CC#N>[CH2:25]([O:28][C@H:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C@@H:31]([NH:40][CH2:13][C@@H:11]([OH:12])[C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:30]1)[CH:26]=[CH2:27]
Reactant: C=CCO[C@H]1C[C@@H](N)c2cc(OC)ccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Temperature: 30 °C
Reaction time: 60 h
Yield: 16 %

Procedure:
Step E (1): A mixture of benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate (1.0 g, 3.0 mmol), cis-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine (657 mg, 3.0 mmol) and LiClO4 (1.60 g, 15 mmol) in CH3CN (10 mL) with was stirred at 30° C. for 2.5 days. The resulting mixture was poured into brine/NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1-20% MeOH (containing 0.1% triethylamine)/chloroform linear gradient) to give two pure diastereomers 265 mg (16% yield) of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer A, first to elute) and 270 mg (16% yield)of benzyl (2S,3R)-4-((1R,3S)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer B, second to elute). Data for diastereomer A: HRMS (M+H)+=553.2534; 1H NMR (500 MHz, DMSO-d6) δ 7.21-7.35 (m, 4H), 7.14-7.21 (m, 2 H), 7.03 (t, J=9.46 Hz, 1H), 6.87-6.99 (m, 3H), 6.83 (dd, J=8.24, 2.14 Hz, 1H), 5.88-6.00 (m, 1H), 5.30 (dd, J=17.09, 1.83 Hz, 1H), 5.14 (dd, J=10.53, 1.98 Hz, 1H), 4.96-5.02 (m, 1H), 4.83-4.95 (m, 2H), 4.75 (t, J=6.41 Hz, 1H), 4.01-4.13 (m, 2H), 3.91-4.00 (m, 1H), 3.72-3.76 (m, 3H), 3.64-3.72 (m, 1H), 3.44-3.53 (m, 1H), 3.06 (dd, J=13.73, 3.05 Hz, 1H), 2.65-2.75 (m, 1H), 2.54-2.65 (m, 2H), 1.92-2.02 (m, 1H), 1.57-1.67 (m, 1H). Data for diastereomer B: HRMS (M+H)+=553.2509; 1H NMR (500 MHz, DMSO-d6) δ 7.20-7.37 (m, 4H), 7.12-7.22 (m, 2H), 6.98-7.13 (m, 1H), 6.86-7.00 (m, 3H), 6.82 (dd, J=8.24, 2.14 Hz, 1H), 5.80-6.05 (m, 1H), 5.30 (dd, J=17.40, 1.83 Hz, 1H), 5.14 (d, J=10.38 Hz, 1H), 4.80-5.03 (m, 3H), 4.74 (t, J=5.95 Hz, 1H), 3.99-4.15 (m, 2H), 3.95 (t, J=6.10 Hz, 1H), 3.62-3.77 (m, 3H), 3.49 (d, J=4.88 Hz, 1H), 3.03 (dd, J=13.89, 3.20 Hz, 1H), 2.54-2.80 (m, 4H), 2.01-2.18 (m, 1H), 1.59-1.76 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]([NH:17][C:18](=[O:37])[C@@H:19]([NH:29]C(OC(C)(C)C)=O)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:16][C:9]([NH:17][C:18](=[O:37])[C@@H:19]([NH2:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)(NC(=O)[C@@H](N)COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
15.09 g of trifluoroacetic acid were added to a solution of 9.0 g of (2S)-N-(α,α-dimethylbenzyl)-3-benzyloxy-2-(t-butoxycarbonylamino)propionamide (prepared as described in Preparation 4) in a mixture of 100 ml of methylene chloride and 2.4 g of anisole, and the whole mixture was stirred for 1 hour at room temperature. At the end of this time, the excess trifluoroacetic acid was distilled off. On adding diethyl ether, the residue gave 8.8 g of the title compound as needles melting at 148°-150° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[N:14]=[C:13]([CH:16]=[O:17])[NH:12][C:11]=3[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[CH3:24][N:12]1[C:11]2[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]=2[N:14]=[C:13]1[CH:16]=[O:17]
Reactant: O=Cc1nc2c(-c3ccccc3)ccc(-c3ccccc3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cn1c(C=O)nc2c(-c3ccccc3)ccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.3 g (11.07 mmol) 4,7-diphenyl-1H-benzimidazole-2-carbaldehyde, 8.60 g (62.0 mmol) anhydrous K2CO3 and 1.1 ml (11.07 mmol) dimethyl sulfate in 30 ml anhydrous DMF was stirred at room temperature for 30 min. The reaction mixture was then poured into 300 ml water, stirred for 10 min and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (3×50 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to give an yellow oil which was triturated with 20 ml methanol at 0° C., filtered while cold, washed with cold (0° C.) methanol (2×10 ml) and dried under reduced pressure. Yield 3.1 g (89.6%). 1H NMR (250 MHz, CDCl3), δ, ppm: 3.74 (s, 3H), 7.47 (m, 10H) 8.04 (d, JHH=7.8 Hz, 2H), 10.1 (s, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCN(C2C=CC(N[C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=CC=2)CC1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 72 h at rt and using 3 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2.4 equiv) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 489.1 [M+H]+; tR=3.73 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:25])[N:5]2[C:10]=1[C:9]([N:11]1[CH:15]=NC=N1)=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[N:6]2.[CH3:26][O:27][C:28]1[CH:29]=C([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH3:25])[N:5]2[C:10]=1[C:9]([NH:11][C:15]1[CH:29]=[C:28]([O:27][CH3:26])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=1)=[N:8][C:7]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[N:6]2
Reactant: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)nc(-n3cncn3)c12
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(-c3ccc([N+](=O)[O-])cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 130 mg (0.39 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 11A in DMF is treated with 111 mg (0.58 mmol) of 3,4,5-trimethoxyaniline and 80 mg (0.58 mmol) of potassium carbonate. The reaction mixture is stirred overnight at 90° C. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice more with toluene and the solvent is removed in vacuo again. The product is extracted by stirring with a little methanol and filtered off with suction.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12]C(=O)C)=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].Cl>C(O)C.O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1c(C)cc(O)cc1C(C)(C)C
Temperature: 0 °C
Yield: 49.8 %

Procedure:
1.05 g of 1,4-diacetoxy-2-t-butyl-6-methylbenzene was dissolved in 10 ml of ethanol and 2 ml of an aqueous solution containing 0.23 g of sodium hydrosulfite and 0.17 g of sodium hydroxide was added dropwise with stirring at 0° C. The reaction solution was neutralized with 1N hydrochloric acid, and then combined with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.44 g of 4-acetoxy-3-t-butyl-5-methylphenol as a pale yellow oil (yield 50%).