Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CCOCC.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:24][CH:25]([OH:27])[CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CC(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC[C@@H](CC(C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)acetic acid (24 mg, 0.049 mmol; Example 130) in ether (0.40 mL) and MeOH (0.10 mL) was added sodium borohydride (9.26 mg, 0.245 mmol) at 0° C. Then the reaction was allowed to warm to rt. After being stirred at rt for 1 h, the reaction was quenched (10% citric acid) and extracted (2×EtOAc). The combined organic layer was washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by RP-HPLC (30 to 70% MeCN/H2O (0.1% TFA), a gradient elution) provided the title compound as the more polar isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>ClCCl>[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:44][N:45]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])[CH2:46][CH2:47]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCC(NC(=O)OC(C)(C)C)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.9 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (384 mg), (4-phenylpiperidin-4-yl)-carbamic acid tert-butyl ester (230 mg), DIPEA (427 μL) and BEP (456 mg) in dichloromethane (10 mL) was stirred at r.t. for 5 d. The solvent was distilled off in vacuo, the residue was re-dissolved in MTBE/ethyl acetate (v/v=1/1, 40 mL) and washed once with water, twice with saturated sodium bicarbonate solution, once with 1N sodium hydroxide solution and with brine. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 95 mg (16%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: OCCN1CCNCC1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: OCCN1CCN(c2nnc3n2-c2ccc(Br)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In a manner given in Example 1, 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-bromo-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:4]([C@H:6]1[N:9]([CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8](=[O:29])[C@@H:7]1[C@H:30]([O:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:31])=[CH2:5])([OH:3])=[O:2].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:43]([O:2][C:1]([C:4]([C@H:6]1[N:9]([CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:8](=[O:29])[C@@H:7]1[C@H:30]([O:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:31])=[CH2:5])=[O:3])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=C(C(=O)O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C(=O)OCc1ccccc1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A solution of (3S,4S)-4-(1-carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (3.7 g) in acetone (60 ml) was treated with benzyl bromide (1.4 g) in the presence of anhydrous potassium carbonate (1.88 g) under reflux for 2 hours. The reaction mixture was cooled down to room temperature, filtered to remove insoluble materials and concentrated in vacuo. The concentrate was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-benzyloxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6]C1=O)([CH3:3])[CH3:2]>C(O)C>[OH:6][C:7]1([CH2:8][NH:4][CH:1]([CH3:2])[CH3:3])[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: CCOC(=O)Nc1ccc2c(c1)OCC1(CO2)CN(C(C)C)C(=O)O1
Solvent: CCO
Product: CCOC(=O)Nc1ccc2c(c1)OCC(O)(CNC(C)C)CO2

Procedure:
This oxazolidinone from Step A above is refluxed in ethanol containing anhydrous hydrogen chloride. The solution is neutralized, evaporated to a small volume, diluted with water and extracted with ether. The dried etheral solution is evaporated to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][C:11](=[O:24])[CH2:12][C:13]1[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH2:22][CH3:23].I[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[N:10]([C:11](=[O:24])[CH2:12][C:13]1[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH2:22][CH3:23])[CH3:27]
Reactant: CCc1cc(C)cc(CC)c1CC(=O)Nc1ncccc1C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1CC(=O)N(C)c1ncccc1C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(2,6-diethyl-4-methyl-phenyl)-acetylamino]-nicotinic acid methyl ester (Example 1.2) (460 mg) in N,N-dimethylformamide (5 ml) was added iodomethane (0.42 ml) at between −5° C. and 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 minutes before the addition of sodium hydride (60 mg) (60% by weight dispersion in mineral oil) in one portion at between −5° C. and 0° C. The reaction mixture was stirred at between −5° C. and 0° C. for 1 hour, and then at ambient temperature for 2 hours. The reaction mixture was partitioned between diethylether and aqueous hydrochloric acid (2M). The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: 10% ethyl acetate/dichloromethane) to give 2-{[2-(2,6-diethyl-4-methyl-phenyl)-acetyl]-methyl-amino}-nicotinic acid methyl ester as a light orange oil (370 mg). 1H-NMR (400 MHz, CDCl3): 8.76 (m, 1H), 8.36-8.38 (m, 1H), 7.44-7.47 (m, 1H), 6.83 (s, 2H), 3.97 (s, 3H), 3.33 (bs, 2H), 3.27 (bs, 3H), 2.47-2.57 (m, 4H), 2.26 (bs, 3H), 1.09-1.12 (m, 6H) ppm.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[C:12]1([C:4]2[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.4 %

Procedure:
To a solution (50 mL) of ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (8.5 g) in ethanol was added 10% palladium carbon (50% containing water, 0.5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a colorless solid (yield 4.50 g, 62%).
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][CH:36]=[C:35]2[O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH3:53])=[CH:47][CH:46]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][CH2:63][C:64]([N:66]=[C:67]=[S:68])=[O:65]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][CH:36]=[C:35]2[O:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH2:52][CH3:53])[C:67]([NH:66][C:64](=[O:65])[CH2:63][CH2:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[O:55][CH3:54])=[S:68])=[CH:47][CH:46]=1
Reactant: COc1ccccc1CCC(=O)N=C=S
Reactant: CCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: COc1ccccc1CCC(=O)O
Agent: O=C(Cl)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=S)NC(=O)CCc1ccccc1OC)c1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N-ethylamine (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methoxyphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 52%).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][N:20]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:25][CH:26]=1)#[N:4]
Reactant: Fc1cccc(CCBr)c1
Reactant: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CNCC(C2)O3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CN(CCc4cccc(F)c4)CC(C2)O3)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To 2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethanesulfonic acid 4-cyano-benzylamide dihydrochloride (0.127 g, 0.30 mmol; prep P above), 1-(2-bromo-ethyl)-3-fluoro-benzene (0.064 g, 0.315 mmol) and potassium carbonate (0.145 g, 1.05 mmol) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was stirred for 20 minutes before it was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 43 mg (30.3%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:16](=[O:19])([O-])[OH:17].[Na+]>C(OCC)(=O)C>[O:19]=[C:16]1[O:17][CH:3]([C:4]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:5])[CH2:2][CH2:15]1
Reactant: O=C([O-])O
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCC(C(=O)Nc2ccccc2C(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4.9 g of 5-oxotetrahydrofuran-2-carboxylic acid and 5.5 ml of thionyl chloride was subjected to reflux for 2 hours. Thionyl chloride was then distilled off under reduced pressure to leave 5-oxotetrahydrofuran-2-carbonyl chloride. This product was mixed with 5.0 g of 2-aminobenzophenone, 200 ml of ethyl acetate and 200 ml of a saturated aqueous solution of sodium hydrogencarbonate, which was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone (6.5 g) as needles, m.p. 100° C.-102° C.
Reaction SMILES: [Li]CCCC.Br[C:7](Br)=[CH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>O1CCCC1>[C:8]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[CH:7]
Reactant: CCCCCCCCC(C=C(Br)Br)CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CCCCCC)CCCCCCCC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
n-BuLi (2.5 M in hexanes, 261 cm3, 652 mmol) is added dropwise over 60 minutes to a solution of 7-(2,2-dibromo-vinyl)-pentadecane (4.1) (117 g, 296 mmol) in anhydrous tetrahydrofuran (1350 cm3) at −78° C. The mixture is stirred for 45 minutes at −78° C. and water (1.3 L) is carefully added. The reaction mixture exotherms to −10° C. and is allowed to warm to 23° C. whilst stirring over 18 hours. The organic phase is separated, washed with brine (1500 cm3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil is passed through a plug of silica eluting with petroleum ether (40-60° C.). The pale yellow oil is further purified by distillation under vacuum (96° C. at 0.85 mmHg) to give the title product as a colourless oil (57.7 g, Yield: 82%). NMR (1H, 300 MHz, CDCl3): δ 2.30 (m, 1H); 2.03 (d, J=2.4 Hz, 1H); 1.44 (m, 8H); 1.27 (m, 16H); 0.88 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20].Cl>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:1]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)C1CCCCN1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(S(=O)(=O)N2CCCCC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pipecolinic acid (0.331 g, 2.56 mmol) is dissolved in 16 mL mixture of water and p-dioxane (1:1) followed by the addition of triethyl amine (0.78 mL, 5.64 mmol), 4-butoxyphenylsulfonyl chloride (0.67 g, 2.69 mmol), and 4-dimethylaminopyridine (0.031 g, 0.25 mmol). The resulting solution is stirred at room temperature overnight. The reaction mixture is acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic extracts are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) 342 (M+ +H, 100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([NH:24][NH:25]C(OC(C)(C)C)=O)=[O:23])[C:10]=2[CH3:33])=[CH:5][CH:4]=1>CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([NH:24][NH2:25])=[O:23])[C:10]=2[CH3:33])=[CH:7][CH:8]=1
Reactant: Cc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: Cc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 40 °C
Yield: 82.7 %

Procedure:
20 ml of 2N ethereal hydrochloric acid are added to a solution of 6.2 g of the compound obtained in stage B in 100 ml of MeOH and then the mixture is heated at 40° C. for 3 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with a 10% NaHCO3 solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is taken up in pentane and the precipitate formed is filtered off. 4.09 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCBr)cc1[N+](=O)[O-]

Procedure:
A round-bottom flask was charged with 4-amino-3-nitrophenol (15.4 g, 0.1 mol, commercially available from Aldrich), acetone (600 mL), 1,2-dibromoethane (34.5 mL, 0.4 mol) and cesium carbonate (39 g, 0.12 mol). The mixture was refluxed 15 hours with stirring. The mixture was filtered to remove the salt, the filtrate was concentrated. Purification by the silica gel chromatography gave 4-(2-bromoethoxy)-2-nitroaniline (6.5 g). 1H-NMR (400 MHz, CDCl3): δ 7.57 (d, 1H), 7.12 (dd, 1H), 6.80 (d, 1H), 5.95 (s, br, 2H), 4.27 (t, 2H), 3.64 (t, 3H). MS (EI): 262 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:51])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.O>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:47]2[CH:48]=[CH:49][C:44]([C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:51])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:45][CH:46]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (46 mg, 0.144 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (78 mg, 0.173 mmol), Pd(PPh3)4 (17 mg, 0.0144 mmol), CuI (5 mg, 0.0288 mmol) and triethylamine (0.200 mL, 1.44 mmol) were suspended in DMF (1.5 mL). The reaction mixture was stirred at 80° C. for 2 hours then 1 mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 24%). 1H NMR (MeOH-d4, 400 MHz) 7.65 (d, J=8.2 hz, 2H), 7.45 (d, J=8.2 hz, 2H), 7.38 (s, 1H), 7.22 (s, 1H), 6.98 (m, 1H), 5.17 (m, 1H), 5.11 (m, 1H), 4.25-4.20 (m, 2H), 4.01-3.79 (m, 4H), 3.66 (s, 6H), 2.37-2.00 (m, 10H), 0.99-0.89 (m, 12H); MS (ESI) m/z 687 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([F:22])[F:21])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C=[O:33])C>Cl[Cu].Cl[Pd]Cl>[F:21][CH:20]([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][C:2](=[O:33])[CH3:3])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1
Temperature: 30 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (379 mg, 1 mmol) in DMF were added CuCl (227 mg, 2.3 mmol) and PdCl2 (53 mg, 0.3 mmol) at 0° C. under O2, and the mixture was stirred overnight at 30° C. The mixture was washed with water and extracted with EtOAc. The organic layer was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (180 mg, 50%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: ClCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1

Procedure:
15 g of 2-tert-butyl-4-piperazin-1-yl-6-propyl-pyrimidine (57.2 mmol), 9 g of 1-bromo-3-chloropropane (57.2 mmol), 8.7 g of triethylamine (86.2 mmol) in 200 ml of acetonitrile were heated to reflux for 3 h. The precipitate was filtered off and the remaining filtrate evaporated to dryness. The thus obtained crude product was purified by chromatography on silica gel with dichloromethane/methanol (0-5%). Yield: 6 g (31%).