Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].C[CH2:42][O:43][C:44]([CH3:46])=O>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH:10]=[CH:11][C:46]([CH2:44][O:43][CH3:42])=[CH:13][CH:8]=2)=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 140 °C

Procedure:
A mixture of [(1S,2S)-1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (78 mg, 0.146 mmol), arylboronic acid (0.18 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (38 mg, 0.27 mmol) in CH3CN/H2O (3.5/0.5 mL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 576).
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(C1C=CC(C2C=CC(OCC(O)=O)=CC=2)=CC=1)#N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCC1COc2cscc2O1
Agent: CN(C)c1ccncc1
Agent: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.73 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 8.08 mmol of EDT-methanol), 1.64 g of N,N′-dicyclohexyl-carbodiimide and 0.13 g of 4-(dimethylamino)pyridine are dissolved in 100 ml of CH2Cl2 and cooled to about 0° C. in an ice bath. 2.00 g of [(4′-cyano-1,1′-biphenyl-4-yl)oxy]acetic acid are added thereto a little at a time over a period of 1 hour while stirring and cooling in ice. The reaction is then continued at 23° C. for 42.5 hours. The N,N′-dicyclohexylurea formed is subsequently filtered off. The filtrate is washed in succession with 2×200 ml of 1 M HCl, 2×200 ml of saturated NaHCO3 solution and 2×200 ml of saturated NaCl solution. The organic phase is dried over MgSO4 and, after the magnesium sulphate has been filtered off, freed of solvent on a rotary evaporator. This gives 3.71 g of crude product which is purified by column chromatography using n-hexane/ethyl acetate 3:2. 0.39 g of the pure ester of EDT-methanol (I-a2) is obtained as colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(F)c1
Reaction time: 8 h

Procedure:
3,5-Difluorobenzoyl chloride (50 mg, 0.28 mmol, CAS RN 129714-97-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired compound as a waxy solid (26 mg, 34%). MS (ESI): m/z=339.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=[CH2:10].[Cl-].[NH4+]>O1CCCC1.O>[CH:1]1([CH:7]([OH:8])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)C1CCCCC1
Temperature: -20 °C
Yield: 37.8 %

Procedure:
A solution of cyclohexanecarbaldehyde (4.79 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (2.11 g, 38%). 1H NMR (300 MHz, CDCl3): δ ppm 1.40 m, 11 H) 3.85 (m, 1 H) 5.17 m, 2 H) 5.86 m, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: N[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@@H](c5ccccc5)CO4)c3)cc12
Yield: 24.2 %

Procedure:
Zinc chloride (9 mg, 0.067 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.135 mmol) and (S)-2-amino-2-phenylethanol (93 mg, 0.675 mmol) in PhCl (3 mL) rt. It was subjected to two interations of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (16 mg, 23%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1H, s), 7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45 (1H, t, J=9.16 Hz), 4.94 (1 H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz), 2.97 (3H, s). LC-MS retention time 1.76 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=18.10 min, purity=99%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[I:22]N1C(=O)CCC1=O>C(#N)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[I:22]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)n1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c(N)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylsulphenylphenyl)pyrazole (10 g) in acetonitrile (50 ml) at room temperature was added N-iodosuccinimide (6.4 g) in acetonitrile (25 ml). After 15 minutes the mixture was evaporated to dryness leaving and the residual buff solid taken up in dichloromethane (300 ml). The solution was washed with water (75 ml, ×3), then brine (50 ml), then dried (MgSO4) and evaporated. Trituration with hexane (100 ml, ×2) to provide the title compound as buff solid m.p. 172-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[F:50][C:51]([F:63])([F:62])[C:52]([N:54]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56](Cl)=[O:57])=[O:53]>ClCCl>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=[C:12]([F:13])[C:2]=1[NH:1][C:56]([CH:55]1[CH2:59][CH2:60][CH2:61][N:54]1[C:52](=[O:53])[C:51]([F:63])([F:50])[F:62])=[O:57])=[O:5]
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)C4CCCN4C(=O)C(F)(F)F)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a scintillation vial was combined 32 mg (0.06 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide and 15 uL (0.09 mmol) of N,N-diisopropylethylamine. To the vial was added 745 μL of a 0.1M solution of (S)-(−)-N-(trifluoroacetyl)prolylchloride in dichloromethane. The reaction was stirred at room temperature for 30 minutes, quenched with a few drops of methanol, and concentrated down. MS: m/z 752.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (30 mg, 0.089 mmol) (from Example 5 supra) and Et3N (24 μL , 0.172 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 4-methoxybenzoyl chloride (17.4 mg, 0.102 mmol) (Fluka). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo3-[(1H-pyrrol-2-yl) methylene]-1H-indol-4-yl]-phenyl]-4-methoxybenzamide (31 mg, 80%) as a brown solid (mp 209-211° C.).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.O[N:15]1[C:19]2C=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=N1.[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]([C:42]([OH:44])=O)=[CH:31][N:30]=1)[CH3:25].NC1C=NC=CC=1>CN(C)C=O.O>[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:32]([C:42]([NH:17][C:18]2[CH:19]=[N:15][CH:21]=[CH:22][CH:23]=2)=[O:44])=[CH:31][N:30]=1)[CH3:25]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)Nc1ncc(C(=O)O)c(Nc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ncc(C(=O)Nc2cccnc2)c(Nc2ccccc2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole monohydrate (0.077 g, 0.500 mmol) were added to a stirred solution of 2-(3-ethylureido)-4-(phenylamino)pyrimidine-5-carboxylic acid (v) (0.100 g, 0.330 mmol) in dimethylformamide (3 mL) at room temperature. After 15 min, 3-aminopyridine (0.047 g, 0.500 mmol) was added and the reaction mixture stirred at 40° C. for 24 h. The mixture was cooled to room temperature, treated with water (2 mL) and the resulting off-white precipitate filtered, washed with water, air-dried and triturated with hot EtOH to give Compound 6 (0.060 g, 0.159 mmol, 48%) as a colourless powder. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (1H, br s), 10.52 (1H, br s), 9.89 (1H, br s), 8.91-8.84 (3H, m), 8.35 (1H, dd, J 1.0 and 4.6), 8.12 (1H, dt, J 2.0 and 8.7), 7.67 (2H, d, J 8.2), 7.46-7.38 (3H, m), 7.20 (1H, t, J 7.2), 3.10 (2H, dq, J 5.6 and 7.2), 0.93 (3H, t, J 7.2); [M+H]+ m/z=378.2.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 75.4 %

Procedure:
In 50 ml of pyridine were dissolved 2.5 g of 5-fluorouracil and 0.35 g of anhydrous aluminum chloride. To this solution were added 2.3 ml of 2,3-dihydrofuran and the mixture was reacted at 120° C. for 6 hours. A part of the reaction liquid was extracted and subjected to thin layer chromatography to observe the state of proceeding of the reaction whereby the composition of the product was 70% of the end product, 10% of by-products and less than 1% of unreacted 5-fluorouracil. The pyridine was distilled off from the reaction liquid and the residue was shaken with 50 ml of chloroform and a small amount of water and the mixture was separated. The chloroform layer was dried and the chloroform was distilled off. The precipitated crystals were collected by filtration, washed with ether and dried to obtain 2.9 g of 1-(2-tetrahydrofuryl)-5-fluorouracil in a yield of 75.4%, which had a melting point of 167°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH:6][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CCSCC
Solvent: CO
Product: CCOC(=O)[C@H](CCSCC)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React L-Ethionine ethyl ester (3.51 g) and 3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that described in Example 1, Step 1 to give a yellow residue. Chromatograph the yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute with ethyl acetate:hexane 2:18 (16L), then ethyl acetate:hexane 3:17. Repeat chromatography of the fractions using ethyl acetate:hexane as eluant to give Isomer A, a white solid (0.89 g), m.p. 84°-90°, [α]D26 =-60.6° (MeOH) and Isomer B (0.82 g), m.p. 79°-84°, [α]D26 =-0.3° (MeOH).
Reaction SMILES: Cl[N:2]1[C:6](=O)[CH2:5][CH2:4]C1=O.[F:9][C:10]1[C:18]([I:19])=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].O.C1(N)CC1>CN(C=O)C>[CH:6]1([NH:2][C:12](=[N:13][OH:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:18]([I:19])[C:10]=2[F:9])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(I)c1F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(NC1CC1)c1cccc(I)c1F
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
N-chlorosuccinimide (1.20 g, 8.9 mmol) was added portionwise to a stirred solution of 2-fluoro-3-iodobenzaldehyde oxime (preparation 22e, 2.15 g, 8.1 mmol) in N,N′-dimethylformamide (3 mL) and the mixture was stirred for 15 minutes at 55° C. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was taken up in tetrahydrofuran (10 mL), cooled by means of an ice-water bath and cyclopropylamine (2.90 mL, 41.9 mmol) was added dropwise. After stirring 3 hours at room temperature, water was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (2.53 g, 96%) as a white 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:29][CH3:30])=[CH:20][CH:21]=[C:22]([C:23]#[C:24][Si](C)(C)C)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:23]([C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:29][CH3:30])=[CH:20][CH:21]=1)#[CH:24]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C#C[Si](C)(C)C)ccc(OC)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A mixture of 17 mg (0.04 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trimethylsilanylethynyl-1H-benzoimidazole and 0.5 ml 1N NaOH in 2 ml THF/methanol (1:1) is stirred for 1 hour at 60° C. The reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified on 0.5 mm silica gel plates (hexane:EtOAc=3:1) to afford 7 mg of the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH:20](C3C=CC(F)=CC=3)[CH2:21][CH:16]2[CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH2:20][CH2:21][CH:16]2[CH2:15]1)([O-:10])=[O:9]
Reactant: NCCC1CC2CC(c3ccc(F)cc3)OC2O1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1NCCC1CC2CCOC2O1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
4Chloro-3-nitropyridine (160 mg, 1.0 mmol) is added to a stirred solution of 5-(2-aminoethyl)-2-(4-fluorophenyl)hexahydrofuro[2,3-b]furan (200 mg, 0.8 mmol) and triethylamine (1.0 ml) in chloroform (15 ml) at ambient temperature. The reaction mixture is stirred overnight, then washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to leave an orange oil. This is purified by chromatography over silica (1:1 ethyl acetate/hexane) to give 2-(4-fluorophenyl)-5-(2-(N-3-nitropyrid-4-ylaminoethyl)hexahydrofuro[2,3-b]furan (175 mg, 59%) as a yellow amorphous solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH3:21]
Reactant: OCc1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(CO)cc1)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Caesium carbonate (39.4 g) was added to a solution of 4-hydroxymethyl-phenol (10 g) and 2-bromo-1,1-diethoxyethane (12.73 mL) in DMF (200 mL) and the resulting mixture stirred at 90° C. for 16 h. The reaction was poured into water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic solutions were washed with water (250 mL) and brine (250 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with an isohexane to diethyl ether gradient to give the subtitled compound as a yellow oil. Yield 9.5 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 h. The N,N-dimethylformamide was evaporated on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 min. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification was carried out. 1.23 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OCCCO
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCCCO)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a solution of 1,3-propanediol (27.8 g, 365 mmol) in dimethylformamide (70 ml). 7-Fluoroquinazolin-4(3H)-one (10 g, 60.9 mmol) was added portionwise and the reaction mixture heated at 60° C., then at 110° C. for 3 hours. The reaction was cooled to 0° C., quenched with water (280 ml) and adjusted to pH 5.9. The resulting suspension was filtered, washed with water then ether and dried over phosphorus pentoxide to afford 7-(3-hydroxypropoxy)quinazolin-4(3H)-one as a white powder (12.41 g, 92% yield):