Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC2OC(C(O)=O)=CC=2C=1)#[N:2].NC1C=CC(CCC(OC)=O)=CC=1.[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:43][CH:42]=3)=[O:39])=[CH:35][C:34]=2[CH:53]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:43][CH:42]=3)=[O:39])=[CH:35][C:34]=2[CH:53]=1)(=[NH:2])[NH2:29]
Reactant: COC(=O)CCc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Agent: COC(=O)CCc1ccc(N)cc1
Product: COC(=O)CCc1ccc(NC(=O)c2cc3cc(C(=N)N)ccc3o2)cc1

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and methyl 3-(4-aminophenyl)propionate (211 mg, 1.18 mmol) were condensed to quantitatively give 371 mg of methyl 3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]phenyl]propionate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[N:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]2[O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25][C:13]=12)=[O:11].C(=O)(O)[O-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:11])[C:12]2[CH:17]=[N:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]3[O:22][C:23]([CH3:26])([CH3:27])[O:24][CH2:25][C:13]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Product: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
A 4-fluorophenyl magnesium bromide solution (0.438 mL of 1M in tetrahydrofuran, 30.0 mmol, 1.1 eq) at −78° C. was added to a methyl 5-formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate solution (0.100 g, 0.398 mmol, 1 eq. in 5.0 mL of tetrahydrofurane). The reaction mixture was stirred for 20 min. at −78° C. A saturated bicarbonate solution was added and reaction mixture was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure yielding 0.065 g of crude product methyl 5-((4-fluorophenyl)(hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate 2a (47% yield) as a white solid.
Reaction SMILES: C(S)C.[H-].[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C=O)C>[CH2:29]([O:28][C:16]1[CH:17]=[C:18]([OH:20])[CH:19]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:15]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(COc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Ethanethiol (10 g, 216 mmol) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 2.4 g, 100 mmol) in dry DMF (120 mL) at 0° C. After 1 h, 1,3,5-tribenzyloxybenzene (24 g, 60 mmol) was added in 10 batches and the mixture was heated to 150° C. for 1.5 h. After the reaction was cooled, water (500 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (benzene) to give 3,5-dibenzyloxyphenol as white solid (11%) after recrystallization from carbon tetrachloride and product #d as white solid (56%) after recrystallization from EtOAc and hexane. Compound #d was identified by mp 107-109° C.; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.23 (m, 15H), 6.25 (d, J=2.2 Hz, 1H), 6.07 (d, J=2.2 Hz, 1H), 4.96 (s, 2H), 4.92 (s, 2 H), 3.99 (s, 2H); 13C NMR (CDCl3, 400 MHz) δ 158.4, 157.9, 154.9, 140.7, 136.7, 136.6, 128.4, 128.2, 128.1, 127.8, 127.5, 127.3, 127.0, 125.6, 108.5, 94.7, 93.3, 70.2, 69.9, 28.3; HRMS (ESI) calcd for C27H24O3Na (M+Na) 419.1623. found 419.1645.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[CH3:44][C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][C:46]=1[CH2:56][C:57]1[O:58][C:59]2[CH:65]=[CH:64][C:63]([CH:66]=[O:67])=[CH:62][C:60]=2[CH:61]=1>ClCCl>[OH:67][C@H:66]([C:63]1[CH:64]=[CH:65][C:59]2[O:58][C:57]([CH2:56][C:46]3[N:47]=[C:48]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:49][C:45]=3[CH3:44])=[CH:61][C:60]=2[CH:62]=1)[C@H:15]([O:16][CH2:17][CH3:18])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:19]
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of (S)-4-benzyl-3-(ethoxyacetyl)oxazolidin-2-one (1.0 g, 3.8 mmol) in dichloromethane (10 ml), cooled to 0° C., was added freshly distilled dibutylboron triflate (1.1 ml, 4.6 mmol) dropwise, followed by triethylamine (0.69 m), 4.9 mmol). After 5 minutes the solution was cooled to -78° C. and a precooled solution of 2-(5-methyl-2-phenyl-4-oxazolyl) methyl-5-benzofurancarboxaldehyde (1.33 g, 4.2 mmol) in dichloromethane (5 ml) was added. After 20 minutes the mixture was warmed to 0° C. and stirred at that temperature for 1 hour then quenched with a solution of pH 7 buffer (10 ml) in methanol (30 ml), followed by a solution of 30% hydrogen peroxide (10 ml) in methanol (30 ml), and stirred at 0° C. for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate, 1:1) and obtained as a yellow solid (1.16 g, m.p. 66° C.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:43]([NH2:45])[CH3:44]>C(Cl)Cl>[CH3:44][CH2:43][NH:45][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CCN
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 169.6 %

Procedure:
Under an atmosphere of nitrogen 250 mL methylenechloride were added to 12.34 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents) and the solution was cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.8 g of pivalic acid chloride (MW=120.58; 48.1 mmol; 1.8 equivalents) were added. The reaction mixture was stirred for two hours. Then a solution of 2.3 g ethylamine (MW=45.08; 2.0 equivalents) in 10 mL of methylene chloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by adding 250 mL of water and adjusting the pH to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layers was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 18.4 g of bimatoprost crude (yield: 95%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][CH:2]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCC(N)c1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCC(NS(=O)(=O)c1ccc(C)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution (10 ml) of ethyl 6-amino-6-(2-naphthyl)hexanoate (1.0 g) and 4-methylbenzenesulfonyl chloride (0.73 g) in THF was added triethylamine (0.39 g) dropwise and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was dried and concentrated and the crude residue was recrystallized from ethyl acetate-hexane to provide the title compound (1.3 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5](Cl)[N:4]=1)#[N:2].[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:20])=[C:5]([P:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:20])[N:4]=1)#[N:2]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: Clc1ccccc1Cl
Product: N#Cc1nc(P(=O)(c2ccccc2)c2ccccc2)c(P(=O)(c2ccccc2)c2ccccc2)nc1C#N
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a stirred, refluxing solution of 5.00 g of 2,3-dicyano-5,6-dichloropyrazine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 10.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 4 hours and then allowed to stand overnight. The resulting solid was separated by filtration, washed with benzene and twice with hexane, recrystallized from 200 ml of o-dichlorobenzene, and dried at 80° C./0.1 mm (13 Pa) to give 8.08 g of 2,3-dicyano-5,6-bis(diphenylphosphinyl)pyrazine (shown by formula in claim 4) as a white solid, decomposition beginning at 210° C. Anal. calcd for C30H20N4O2P2 : C, 67.93; H, 3.80; N, 10.56; P, 11.68. Found: C, 67.77; H, 3.92; N, 10.48; P, 11.18.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][OH:14])=[N:10][CH:11]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:10][CH:11]=1
Reactant: COCOCc1ccc(CCO)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Yield: 78.5 %

Procedure:
To a solution of 2-(5-methoxymethoxymethyl-2-pyridyl)ethanol (11.6 g) and 4-fluoronitrobenzene (8.5 g) in N,N-dimethylformamide (100 ml) was added by portions sodium hydride in oil (60%, 2.8 g) with ice-cooling. The reaction mixture was stirred with ice-cooling for additional 1 hour, poured into water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-methoxymethoxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (14.7 g, yield: 79%) as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([CH3:21])[C:7]=1[CH:8]1[C:12](=[O:13])[C:11](=[CH:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][C:9]1=[O:20].[H][H]>CO.[Pd]>[CH3:21][C:6]1[CH:5]=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[CH:8]1[C:12](=[O:13])[CH:11]([CH2:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][C:9]1=[O:20]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(=CC2CCOC2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(CC2CCOC2)C1=O
Yield: 41.4 %

Procedure:
To a solution of 2-(3,5-dimethylbiphenyl-4-yl)-4-[1-(tetrahydrofuran-3-yl)methylidene]-cyclopentane-1,3-dione (0.29 g, 0.8 mmol) in methanol (10 ml) is added 10% palladium on carbon (0.06 g), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(3,5-dimethylbiphenyl-4-yl)-4-(tetrahydrofuran-3ylmethyl)-cyclopentane-1,3-dione (0.12 g).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[S:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[S:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: S=C(NCC1CCCCC1)NCC1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=S)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of cyanoacetic acid (Aldrich, 1.23 g, 14.3 mmol) and 1,3-bis(cyclohexylmethyl)thiourea (from step (a), 3.50 g, 13.0 mmol) in acetic anhydride (8.1 mL) was stirred at 70° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil was dried by evaporation of portions of 10% water-ethanol (3×50 mL). The resulting solids were dissolved in ethanol (12 mL)-water (28 mL) at reflux with adjustment of the pH to 11 by addition of 10% aqueous sodium carbonate. After 1 h, the mixture was cooled to ambient temperature, volatiles were removed under vacuum, and the residue was chromatographed on silica gel. 6-Amino-1,3-bis(cyclohexylmethyl)-1,2-dihydro-2-thioxo-4(3H)-pyrimidinone eluted with 4% methanol in chloroform, and was recrystallized from 2% ethyl acetate in hexanes to provide an off-white powder (2.27 g, 50%), m.p. 147°-150° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]([NH:15][NH2:16])=[O:14])=[CH:5]1.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[O:14][C:2]([NH2:1])=[N:16][N:15]=2)=[CH:5]1
Reactant: NNC(=O)c1c[nH]c2ncccc12
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(-c2c[nH]c3ncccc23)o1
Yield: 78.8 %

Procedure:
360.8 mg of cyanogen bromide is added dropwise with stirring to a mixture of 500 mg of 1-(1H-pyrrolo[2,3-b]pyridine-3-carbohydrazide, 1.192 g of sodium hydrogencarbonate in 50 ml of water and 5 ml of DMF. The reaction mixture starts to foam, and a fine precipitate forms. This is filtered off with suction after 2 hours and dried, giving 450 mg of 5-(1H-pyrrolo[2,3-b]-pyridin-3-yl)-1,3,4-oxadiazol-2-ylamine (yield: 78.8%); MS-FAB (M+H+)=202.2; Rf (polar method): 1.00 min;
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:14][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].C1CCN2C(=NCCC2)CC1>CC#N>[O:33]=[C:32]1[O:1][N:2]=[C:3]([CH:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:12][CH:13]([NH:15][C:16]([CH2:18][NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[O:17])[CH2:14]3)[CH2:7][CH2:6]2)[NH:4]1
Reactant: N=C(NO)C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3noc(=O)[nH]3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above intermediate from Step B (0.044 g, 0.1 mmol), 1,1′-carbonyldiimidazole (Aldrich, 0.0178 g, 0.11 mmol), DBU (Acros, 0.06 mL, 0.4 mmol) in CH3CN (1 mL) was stirred at rt overnight. The crude product was purified by HPLC to give a TFA salt as a yellowish solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[F:19])[O:8][N:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[C:12]([F:19])[CH:13]=1)#[N:18]
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2F)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester by treatment with aqueous NaOH solution in tetrahydrofuran. LC (method 18): tR=0.32 min; Mass spectrum (EI): m/z=232 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-benzonitrile (CAS Reg. No. 17201-43-3). Light brown powder (65%). MS (Turbo Spray): m/z=492.2 (M+H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]=[CH:2]1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH:2]=[CH:3]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1C=CC(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1C=CC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 34 (79 mg, 0.69 mmol) in DMF (1 mL) was added sodium hydride (14 mg, 0.62 mmol) at 0° C. Benzyl bromide (73 μL, 0.62 mmol) was added to the mixture dropwise, under an argon atmosphere. The reaction was stirred for 16 h at room temperature. Upon completion, distilled water (3 mL) was added to the mixture and the organic layer extracted into ethyl acetate. The organic layers were combined, dried and concentrated to give a crude mixture that was purified by column chromatography (Silica gel, 10%-20% EtOAc in hexane) to give 35 as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (175 mg), hydroxylamine hydrochloride (50 mg), potassium carbonate (70 mg), ethanol (1 mL), and water (1.5 mL) is heated under reflux for 2 h. The reaction mixture is concentrated in vacuo and chromatographed on silica gel (dichloromethane/methanol 92:8→60:40) to give the title compound. LC (method 5): tR=0.65 min; Mass spectrum (ESI+): m/z=417 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O>CC(O)=O.[Fe]>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)c([N+](=O)[O-])c1
Temperature: 110 °C

Procedure:
To a stirred solution of p-xylene (10.4 g, 97.9 mmol) in concentrated sulfuric acid (20 mL), cooled in an ice bath, was added 90% nitric acid (12.4 mL, 264 mmol) dropwise over 50 min. The resulting mixture was heated to 80° C. for 2 h, then poured onto ice and extracted with CH2Cl2 (2×400 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40. The resulting solid was recrystallized from CH2Cl2 to yield 2,5-dimethyl-1,3-dinitrobenzene. 2,5-Dimethyl-1,3-dinitrobenzene (3.68 g, 18.8 mmol) was dissolved in AcOH (35 mL) and iron powder (1.95 g, 34.9 mmol) was added. The mixture was heated to 110° C. for 3 h, then filtered through a pad of Celite, washing with EtOAc and H2O. The filtrate was concentrated in vacuo to remove most of the solvent and the residue was partitioned between saturated aqueous NaHCO3 (200 mL) and EtOAc (200 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=167 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([Cl:69])[CH:63]=2)[C@@H:59]([C@H:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([Cl:69])[CH:63]=2)[C@@H:59]([C@@H:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (141 mg, 0.53 mmol) in THF (8 mL) at 0° C. were added 5-chloro-pyridin-2-ol (47 mg, 0.36 mmol) and then DBAD (90 mg, 0.39 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (81 mg, 0.24 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 88 mg (81%) of the title compound as a colorless oil. ES-MS m/e: 446.2 (M+H+).