Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]3)[C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c2ccccc12
Temperature: 90 °C
Yield: 48.4 %

Procedure:
To the solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.15 g, 5.71 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-3-carboxylic acid, methyl ester (1.0 g, 5.71 mmol) in dimethylformamide (5.0 mL) under argon was added finely ground potassium carbonate (1.93 g, 14.0 mmol). The reaction mixture was heated at 90° C. for 4 hours and cooled to ambient temperature. It was diluted with ethyl acetate and filtered. The filtrate was washed with water, 10% citric acid, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield a colorless foam. It was purified by flash chromatography (5% ethyl acetate in hexanes) to give 1-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-1H-indole-3-carboxylic acid, methyl ester (990 mg), m.p. 177°-180° C. (ether-hexanes): 1H NMR (DMSO-d6) δ 8.3 (s, 1 H), 8.21 (d, J=6.4 Hz, 1 H), 7.80 (dd, J=8.8 and 2.4 Hz, 1 H), 7.35 (m, 3 H), 7.18 (d, 8.2 Hz, 1 H), 6.90 (d, J=1.7 Hz, 1 H), 6.42 (s, 1 H), 3.93 (s, 3 H), 1.68 (s, 6 H); 13C NMR (DMSO-d6) 164.5, 156 9, 136.9, 135.5, 135.2, 130.9, 128.7, 126.7, 126.3, 123.8, 122.7, 121.4, 119.8, 118.8, 118.4, 111.6, 108.4, 103.7, 79.3, 51.3, 27.9 ppm; IR (KBr) 2224, 1705, 1207 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCOCC.[CH2:17]1[CH2:22][O:21][CH:20]=[CH:19][CH2:18]1>C(Cl)Cl>[O:21]1[CH2:22][CH2:17][CH2:18][CH2:19][CH:20]1[O:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=S(=O)(Cl)c1cccc(O)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccc(OC2CCCCO2)c1

Procedure:
The synthesis of HIV protease inhibitor UIC-98-056 with hydroxyethylene and hydroxyethylamine isosteres is outlined in FIG. 3. The known lactone 1 was converted to acid 2 by lithium hydroxide mediated hydrolysis followed by protection of the alcohol functionality as tert-butyldimethylsilyl ether (Ghosh et al., 1998, Synthesis, 937 (Review); Ghosh et al., 1991, J. Org. Chem. 56:6500; Evens et al., 1985). The previously described (Ghosh et al., 1992, J. Chem. Soc., Chem. Co., 273; Ghosh et al., 1998, Synthesis, 937 (Review)) azido epoxide 3 was reacted with isobutylamine in 2-propanol at 80° C. for 4 h and the resulting azidoalcohol was treated with m-tetrahydropyranyloxybenzenesulfonyl chloride 4 (Metanilic acid was diazotized at 0° C. and the resulting salt was boiled with water to obtain 3-hydroxybenzene sulfonic acid which was then treated with thionyl chloride/catalytic DMF/reflux to obtain sulfonyl chloride. The hydroxy group of the resulting 3-hydroxybenzene sulfonyl chloride was protected as THP ether by treating with DHP/catalytic PPTS in methylene chloride to get 4 as an oil.) in the presence of aqueous NaHCO3 to provide the sulfonamide derivative 5. The azide functionality of 5 was hydrogenated over 10% Pd—C in methanol to afford the corresponding amine which was coupled with the acid 2 in the presence of 1-[3-dimethylaminopropyl]-3-ethylcarodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) to afford the amide 6. Removal of the BOC group by treatment with aqueous hydrochloric acid and alkoxycarbonylation of the resulting amine with the known (Ghosh et al., 1993a) mixed active carbonate 7 in methylene chloride in the presence of 3 equivalents of triethylamine (Et3N) 23° C. for 12 h afforded the inhibitor 8 (UIC-98-056).
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([C:8]1C=CC=CC=1)C1C=CC=CC=1.C(OC(OCC)CBr)C.Br.C([O-])(O)=O.[Na+]>C(O)(C)C.O>[F:21][C:20]1[C:15]2[N:16]([CH:8]=[CH:1][N:14]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccnc1N=C(c1ccccc1)c1ccccc1
Agent: Br
Agent: CCOC(CBr)OCC
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Product: Fc1cccn2ccnc12
Temperature: 90 °C

Procedure:
A mixture of crude benzhydrylidene(3-fluoropyridin-2-yl)amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 ml) were heated to 90° C. for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), NaHCO3 (68 g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to 50° C. for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2×440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear (1 l ). The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous NaHCO3 solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2×220 ml). The combined organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo affording crude 8-fluoroimidazo[1,2-α]pyridine. Purification was achieved by dissolving the crude material in EtOAc (1 l) and extracting with 2 N hydrochloric acid (5×50 ml). The acid washings were back-extracted with EtOAc (3×100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5×100 ml). The combined organic fractions were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 8-fluoroimidazo[1,2-α]pyridine (11.4 g, 76% from 2-chloro-3-fluoropyridine): δH (400 MHz, CDCl3) 6.69-6.74 (1H, m), 6.84-6.87 (1H, m), 7.65-7.66 (2H, m), 7.97 (1H, dd, J 1.0 and 6.8); m/z (ES+) 137 (100%, [MH]+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: S=C=S
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
(i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2 g.) in ethanol (75 ml.) was added slowly, with stirring, to carbon disulphide (200 ml.). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((4-methyl-5-imidazolyl) methylthio)ethyl]dithiocarbamic acid (9.8 g.), m.p. 127°-129°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[Br:36])=[O:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCCC>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[Br:36])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncn(COCc3ccccc3)c2c1
Reactant: CON(C)C(=O)c1sccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc2nc(C(=O)c3sccc3Br)n(COCc3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 32.1 %

Procedure:
To a stirred solution of 1-benzyloxymethyl-6-methoxy-1H-benzoimidazole (1.00 g, 3.72 mmol, Example 2A) in anhydrous tetrahydrofuran (15 mL) at −78° C. under nitrogen is added n-butyllithium (1.80 mL of a 2.5 M solution in hexanes, 4.5 mmol) over 8 minutes and the resulting yellow solution is stirred a −78° C. After 25 minutes, a solution of 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide (1.03 g, 4.12 mmol) in tetrahydrofuran (10 mL) is added over 20 minutes, to the reaction at −78° C. The reaction is allowed to gradually warm to ambient temperature overnight. The reaction is poured into 10% aqueous ammonium chloride (75 mL) and the mixture extracted twice with ethyl acetate (50 mL). The organic layer is washed with water and brine successively, dried over magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The crude material is chromatographed on silica, eluting with 30% ethyl acetate/heptane followed by 40% ethyl acetate/heptane, to give a waxy solid. Trituration with 25% ethyl acetate/heptane afforded 546 mg (32%) of (1-benzyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)-(3-bromo-thiophen-2-yl)-methanone, as a powder: TLC Rf 0.43 (silica, 40% ethyl acetate/heptane); LC/MS: (M+H 457, RT=3.85 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 8.14 (d, 5.2 Hz, 1H), 7.76 (d, 9.0 Hz, 1H), 7.36 (d, 5.0 Hz, 1H), 7.29-7.20 (m, 6H), 7.04 (dd, 2.5, 9.0 Hz, 1H), 6.13 (s, 2H), 4.59 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:7][CH2:6][C:3]2([C:2]([F:9])([F:8])[F:1])[CH2:5][CH2:4]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: OCC1(C(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methanol (7 g, 50 mmol) and 4-methylbenzene-1-sulfonyl chloride (10.4 g, 55 mmol) in anhydrous DCM (100 mL) with TEA (10 g, 100 mmol) and N,N-dimethylpyridin-4-amine (0.6 g, 5 mmol). Stir at RT overnight. Wash the mixture successively with HCl (2M), saturated NaHCO3, and brine, dry over Na2SO4 and concentrate under reduced pressure to give the title compound (12 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 4.13 (s, 2H), 2.43 (s, 3H), 1.08-1.05 (m, 2H), 0.96-0.94 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2F)=N/O)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2F)=N/O)ccc1=O

Procedure:
In analogy to example 166, step 1, (E)-5-(3-(4-bromophenyl)-3-(2-fluorophenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (example 243, step 5) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a light brown solid, MS (ESI−): m/z=469.1 [M−H]−.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][C:22]([F:29])([F:28])[C:23]([O:25]CC)=[O:24])=[N:6][CH:5]=1>C1COCC1.C(O)C.O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][C:22]([F:29])([F:28])[C:23]([OH:25])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)C(F)(F)Sc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-n2c(Br)cnc2SC(F)(F)C(=O)O)c2ccccc12
Reaction time: 4 h

Procedure:
Aqueous lithium hydroxide solution (1M, 2 eq) was added to a solution of ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate (1 eq) in THF, ethanol and water, and stirred for 4 h. After concentrating, the residue was acidified with aqueous HCl solution (1N), diluted with water and filtered to afford 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetic acid.
Reaction SMILES: [Br-].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:22]1[C:30]2[CH2:29][CH2:28]O[CH2:26][C:25]=2[CH:24]=[CH:23]1.Cl.[CH3:32][O:33][C:34](=[O:44])[C@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43])[NH2:36].C(N(C(C)C)CC)(C)C>C(#N)C.CCCCCC.C(OCC)(=O)C>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C@H:35]([N:36]1[CH2:28][CH2:29][C:30]2[S:22][CH:23]=[CH:24][C:25]=2[CH2:26]1)[C:34]([O:33][CH3:32])=[O:44]
Reactant: COC(=O)[C@@H](N)c1ccccc1Cl
Reactant: c1cc2c(s1)CCOC2
Agent: Cl
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 47.5 g of triphenylphosphine dibromide in 250 ml of acetonitrile, 10 g of 6,7-dihydro-4H-thieno[3,2-c]pyrane was added. The resulting mixture was refluxed for 24 hours, and then added thereto dropwise was a solution obtained by dissolving 14 g of (S)-(+)-2-(2-chlorophenyl)glycine methyl ester hydrochloride and 36 mL of diisopropylethylamine in 100 mL of acetonitrile over 30 minutes while allowing the resulting mixture to reflux. After 8 hours, the reaction product solution was concentrated by evaporation under reduced pressure. To the residue thus obtained, 50 mL of ethyl acetate and 150 mL of n-hexane were added, and the solids thus precipitated were filtered. The filtrate was washed twice with 150 mL portions of water and then with 50 mL of saturated sodium chloride solution. The organic layer was passed through an activated carbon layer and condensed under reduced pressure to obtain 18.6 g (yield of 81%) of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:11][C:10]1[C:6]2[C:4](=[O:3])[N:14]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12][C:7]=2[NH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCC1
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A stirred solution of 4-methyl-2-[2-(2-pyrrolidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (1.441 g, 4.92 mmol) in 22.5 ml of toluene was added dropwise slowly with 2M trimethyl aluminum in toluene (5.1 ml, 10.2 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to 0° C., added with 1N hydrochloric acid (20 ml) dropwise and cold water (20 ml), and stirred for 5 minutes. The mixture was adjusted to pH12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (40 ml×3). The combined organic extracts were filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (719 mg, 59.2%) as a brown oil which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl[S:11]([C:14]1[N:23]=[C:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][N:16]2[N:15]=1)(=[O:13])=[O:12].N1C=CC=CC=1.CS(C)=O>CCCCCC.C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][S:11]([C:14]1[N:23]=[C:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][N:16]2[N:15]=1)(=[O:12])=[O:13]
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Yield: 52.6 %

Procedure:
2,6-Dichloroaniline (2.78 g, 17.2 mmol), 2-chlorosulfonyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (2.0 g, 8.6 mmol), and 30 mL of dry acetonitrile were placed in a 100 mL flask equipped with a gas inlet adapter and a magnetic stirring bar. Pyridine (1.39 mL, 17.2 mmol) and dimethyl sulfoxide (0.15 mL, 2.2 mmol) were added with stirring under nitrogen and the mixture was allowed to react for 1.0 hr. The volatiles were then removed by evaporation under reduced pressure and the residue was dissolved in 200 mL of methylene chloride. The solution obtained was extracted 2 times with 100 mL of 1N HCl and once with 100 mL of water, dried over MgSO4, filtered, and concentrated by evaporation under reduced pressure to obtain a white solid. This solid was stirred with 200 mL of hexane and filtered to give 1.62 g (52 percent yield) of the title compound as a white solid melting at 126°-129° C. (d).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([C:20]([C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)=[O:21])[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(N(C)C)=CC=CC=1)(C)(C)C>[O:21]=[C:20]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:6]3[C:7]2=[C:2]([CH:3]=[CH:4][CH:5]=3)[N:23]2[CH2:24][CH2:25][CH2:26][C@H:22]12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CCCN2)c2c(Cl)cccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)[C@H]3CCCN3c3cccc(c32)C1
Temperature: 25 °C
Yield: 34 %

Procedure:
65 mg of (R)-tert-butyl 9-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was stirred together with 1.8 mg of 2′-(ditert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2.5 mg Pd2(dba)3 and 19 mg sodium 2-methylpropan-2-olate at 100° C. over 10 hours in toluene. The reaction mixture was then cooled to room temperature and evaporated. The residue was purified by column chromatography on silica (eluent: 10-25% ethyl acetate in heptane) to yield 20 mg of the title compound as a beige solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:35][CH3:36])=[CH:20][C:21]([CH:23](OS(C)(=O)=O)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:35][CH3:36])=[CH:20][C:21]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OS(C)(=O)=O)c3ccccn3)cc(OC)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccn3)cc(OC)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a solution of ca. 250 mg of methanesulfonic acid [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-pyridin-2-yl-methyl ester in 7 ml THF, 50 mg LiAlH4 are added. The mixture is heated to reflux temperature and stirred for 3 h. After that the reaction mixture is allowed to cool to room temperature and 1N NaOH solution is added and this mixture is stirred for 30 min and filtered. The filtrate is extracted with ethyl acetate (3×). The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (CH2Cl2:MeOH=95:5) to afford 40 mg of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:20]([NH:27][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(Br)c2)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(NCc3ccccc3)c2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Under argon, 95.0 g (274.8 mmol) of tert-butyl 1-(3-bromo-4-chlorobenzyl)cyclopropanecarboxylate, 36.0 ml (330.0 mmol) of benzylamine, 12.58 g (13.7 mmol) of tris(dibenzylideneacetone)dipalladium, 31.69 g (329.8 mmol) of sodium tert-butoxide and 6.85 g (5.29 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added in succession to 633 ml of dry toluene. The reaction mixture was stirred at 110° C. for 3.0 h and then at RT overnight. The reaction mixture was then filtered off with suction through kieselguhr, and the residue was washed thoroughly with toluene and ethyl acetate. The combined filtrates were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). This gave 50.0 g of the title compound (48.9% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.C(Cl)Cl.CS(C)=O.C(N(CC)CC)C>CCCCCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Yield: 83 %

Procedure:
Alternatively, a mixture of 1-(4-(4-chlorophenyl)-2-hydroxybutyl)imidazole (1.8 kg, 7.18 mol), 2.25 equivalents of pyridine-sulfur trioxide complex and methylene chloride (8.6 L) stirred in the presence of excess dimethyl sulfoxide (19 L) and triethylamine (9 L) at 20°-35° C. for 3 hours. Upon completion of reaction, the mixture was combined with water (76 L) and hexane (34.4 L). The product was isolated, washed with water and hexane and dried to yield 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one, 1.48 kg (83% yield).