Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-chloroacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](Br)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorophenyl)-3-bromopyrazolo[1,5-α]pyridine (0.2 g, 0.68 mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in dry toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.03 g, 0.03 mmol) and the mixture was heated at reflux temperature under a nitrogen atmosphere for about 48 hours. The mixture was cooled to room temperature and diluted with diethyl ether (40 mL). The mixture was poured into a 10% aqueous solution of potassium fluoride (20 mL) and the mixture was stirred for 1 hour. The biphasic mixture was filtered through a pad of diatomaceous earth and the organic phase was separated. The aqueous phase was extracted with diethyl ether (10 mL) and the combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified using silica gel chromatography with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes, as eluent to give the title compound as an off white solid, 0.16 g (80%). 1H NMR (CDCl3) δ 8.58 (br s, 2H), 8.50 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27–7.20 (m, 3H), 7.06 (t, 2H, 8.7 Hz), 6.86 dt, 1H, J=7, 1 Hz). MS (+ve ion electrospray) 290 (100), (MH+).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]=O.Cl>C(O)C.O.CS(C)=O>[CH3:3][O:4][C:5]([CH2:20][OH:1])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=O
Reactant: [OH-]
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: COC(CO)(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Potassium hydroxide 0.4 g was dissolved in ethanol 5 mL and dimethyl sulfoxide 200 mL was further added to obtain a solution. Benzoin methyl ether 30 g (0.13 mol) was dissolved in the solution and paraformaldehyde 5 g (0.16 mol) was added and reacted at 40° C. for 3 hours under nitrogen current. After that, the reaction product was cooled to a room temperature and neutralized with a dilute hydrochloric acid and then saturated salt water 120 mL was added. The solution was extracted by ethyl acetate and the extracted liquid was washed with saturated salt water three times. The washed product was dried and concentrated by anhydrous magnesium sulfate and recrystallized by diethyl ether. α-methylol benzoin methyl ether (MBME) was obtained in such a manner.
Reaction SMILES: FC(F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:46]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].O=[CH:72][CH2:73][CH2:74][C:75]([OH:77])=[O:76].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:75]([CH2:74][CH2:73][CH2:72][N:10]([CH3:9])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:50]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:77])=[O:76]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
11.5 mg (12 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-{[4-(methoxycarbonyl)benzyl]oxy}-3-phenylpropane-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 46) were dissolved in 0.7 ml of dioxane/water (1:1) and treated in analogy to example 1 with 15 aqueous solution of 4-ketobutyric acid in the presence of sodium cyanoborohydride. Following lyophilization from dioxane, the yield was 8.3 mg (74% o. th.) of the title compound in the form of a white solid substance.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
AIBN (1.0 mg, 6.1 μmol) was added to a stirring solution of NBS (4.6 mg, 0.026 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (11 mg, 0.024 mmol) in CCl4 (1 mL). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (3.4 mg, 0.028 mmol) and subjected to microwave irradiation (150° C.) for 5 min. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (7.5 mg, 0.016 mmol, 66% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.84 (1H, s), 8.79 (1H, s), 8.65 (1H, s), 8.19-8.26 (3H, m), 7.89-7.97 (2H, m), 7.59-7.67 (1H, m), 7.54 (2 H, t, J=8.55 Hz), 7.42 (2H, d, J=7.93 Hz), 7.30 (2H, t, J=7.63 Hz), 7.13-7.23 (1H, m), 1.71 (6H, s). LC-MS retention time: 1.75 min; m/z (MH+): 479. 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.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 5-chloro-2-methoxybenzoyl chloride (2.05 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.45-7.76 (m, 2H), 12.43 (s, 1H). MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:64])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[N:58][CH:57]=1.C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:64])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[N:58][CH:57]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)c1cncc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1cncc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), 5-formyl-nicotinic acid methyl ester (0.089 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide (the title compound as an off-white foam (0.113 g, 90%). 1H NMR (CDCl3, 30 MHz) δ 1.21-1.43 (m, 1H), 1.61-1.71 (m, 1H), 2.04-2.13 (m, 2H), 2.32 (s, 3H), 2.71-2.83 (m, 1H), 3.10-3.18 (m, 1H), 3.89 (s, 3H), 4.14 (s, 3H), 4.32-4.50 (m, 2H), 4.83-5.10 (m, 2H), 5.64-5.0 (m, 1H), 6.89 (s, 1H), 7.21 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H), 8.35 (s, 1H), 8.83 (s, 1H), 9.12 (s, 1H); ESI MS m/z 702 [C31H28F9N7O2+H]+
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:31])[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[CH:9][C:10]=1[O:11]C.C(N(CC)CC)C.B(Br)(Br)[Br:40].CO>ClCCl>[BrH:40].[BrH:40].[OH:31][CH:19]([CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:7]1[CH:6]=[C:5]([OH:4])[C:10]([OH:11])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCNCCCC(O)CCNCCc2ccccc2)cc1OC
Reactant: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Br
Product: Oc1ccc(CCNCCCC(O)CCNCCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dihydrochloride from step (c) (2.2 g) in dry dichloromethane (100 ml) was treated with triethylamine (1.3 ml, 0.94 g) and stirred under nitrogen for 15 minutes. The resulting suspension was cooled to -70°, boron tribromide (2.2 ml, 5.85 g) added and the mixture allowed to warm to ambient temperature with stirring over 18 hours. Methanol (10 ml) was added, the resulting solution evaporated to dryness and the solid residue recrystallised from 2-propanol giving the title compound (2.2 g), as the dihydrobromide salt, colorless needles mp 137°-139°.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1([C:15]2[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]1=[O:14].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O>[NH2:3][C:4]1([C:15]2[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:34]([C:27]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=2[O:25][CH3:24])(=[O:36])=[O:35])[C:5]1=[O:14]
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
3.2 g (79 mmol) of sodium hydride (60% dispersion in mineral oil) were added in portions to a solution of 20 g (66 mmol) of 3-amino-5-chloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 50 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 18.7 g (79 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (120 g Redisep cartridge, mobile phase gradient from 2 to 25% dichloromethane in ethyl acetate). 34 g of the title compound were obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[C:8]([F:19])[C:7]=1[F:20])[CH3:4].[CH3:21]I.Cl>CCCCC.C1COCC1.O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][O:18][CH3:21])=[CH:14][CH:13]=2)=[C:8]([F:19])[C:7]=1[F:20])[CH3:4]
Reactant: CCOc1ccc(-c2ccc(CO)[se]2)c(F)c1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(COC)[se]2)c(F)c1F
Reaction time: 2 h

Procedure:
400 mg (10.0 mmol) of sodium hydride (60% suspension in paraffin oil) are washed with n-pentane and suspended in 5 ml of THF. A solution of 1.9 g (about 6.0 mmol) of crude [5-(4-ethoxy-2,3-difluorophenyl)selenophen-2-yl]methanol in 20 ml of THF is added dropwise, and the mixture is stirred for 2 h. 1.0 ml (16.1 mmol) of methyl iodide is metered in, and the batch is stirred at RT for 2 h. Water is carefully added to the reaction mixture, which is then acidified using 2 N hydrochloric acid. The mixture is extracted with MTBE, and the extract is washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and MTBE. 2-(4-Ethoxy-2,3-difluorophenyl)-5-methoxymethylselenophene is obtained as a solid having an m.p. of 84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccc(Cl)cc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN1C(=O)c2ccc(Cl)cc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 107.8 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(6-chloro-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.23 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.135 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.19 g); mp 220° C.; MS: m/z=549(M+1); NMR: 1.73 (m,4), 2.09 (m,2), 2.5 (broad,2), 2.44 (m,2), 2.75 (s,1), 3.07 (m,9), 3.56 (m,4), 4.88 (d,1, J=3), 6.83 (d,1, J=8), 7.08 (s,1), 7.49 (m,3), 8.04 (m,1). Analysis for C27H31Cl3N4O4 : Calculated: C, 52.87; H, 5.75, N, 9.13; Found: C, 53.27; H, 5.64; N, 8.85.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.CO.COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCNC(=O)c2ccc(N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Solvent: CO
Product: CCN1CCNC(=O)c2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C

Procedure:
Into a microwave vial, 8-amino-1-ethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (75 mg, 0.00036 mol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (113 mg, 0.332 mmol), 4 M of hydrogen chloride in dioxane (0.2 mL), and 2-methoxyethanol (2.3 mL) were added. The reaction was then heated in microwave at 120 degree Celsius for one hour. MP-carbonate (3.16 mmol/g loading; 263 mg, 0.83 mmole) and methanol (10 mL) were added. The mixture was stirred at room temperature over night. The solid was filtered and washed with methanol. The desired product was isolated via column chromatography with DCM and methanol as eluant. The collected fractions afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a yellow solid (35 mg, 19%). 1H-NMR (DMSO-D6, 400 MHz): δ 9.19 (s, 1H), 7.94 (s, 1H), 7.51 (d, 1H), 7.12 (d, 1H), 7.07 (d, 1H), 6.97 (s, 1H), 6.75 (d, 1H), 5.99 (bs, 1H), 3.70-3.88 (m, 1H), 3.25-3.52 (m, 7H), 2.92 (s, 3H), 1.97-2.10 (m, 2H), 1.69 (bs, 2H), 1.15-1.48 (m, 4H), 1.08 (t, 3H) LCMS (ESI+) 508.26 (M+H). MP 216-220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
N-Benzyloxycarbonyl-L-alanine (6.5 g, 28.5 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 36.2 mmol), and N-hydroxybenzotriazole (4.8 g, 34.8 mmol) were dissolved in THF (32 mL) and cooled to 0° C. under N2. Diisopropylethylamine (12.3 mL, 71.3 mmol) was slowly added, maintaining the temperature below 25° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.0 g, 36.2 mmol) was then added slowly, maintaining the temperature at 15-25° C. The slurry was stirred overnight at room temperature, and then cooled to 0° C. 1N Aqueous HCl (36 mL) was added slowly, and the mixture was warmed to room temperature and extracted with EtOAc. The combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, and then concentrated and purified by silica gel chromatography to give the desired product as a white solid (6 g).
Reaction SMILES: [F:1][S:2]([C:5]([F:10])([F:9])[C:6](F)=[O:7])(=[O:4])=[O:3].Cl.[C:12]([O:17][CH2:18][CH2:19][NH2:20])(=[O:16])[C:13]([CH3:15])=[CH2:14].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:12]([O:17][CH2:18][CH2:19][NH:20][C:6](=[O:7])[C:5]([F:10])([F:9])[S:2]([F:1])(=[O:4])=[O:3])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)C(F)(F)S(=O)(=O)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A 500 ml flask was charged with CH2Cl2 (80 ml) under nitrogen stream and stirred for 10 min at 0° C. and then 2-(fluorosulfonyl)difluoroacetyl fluoride (29.9 g, 166.0 mmol, 1.5 equivalent (eq.)) was added. After 25 minutes, a CH2Cl2 (160 ml) solution of 2-aminoethyl methacrylate hydrochloride (18.4 g, 111.0 mmol, 1.0 eq.) and pyridine (17.5 g, 221.0 mmol, 2.0 eq.) was added drop wise to the mixture over 50 minutes. The mixture was allowed to warm to room temperature (RT) and stirred for 3 hours at RT. 1N HCl was added to the final reaction mixture and the lower layer was separated and washed with 1N HCl and Brine. The solution was dried over anhydrous MgSO4, filtrated and then CH2Cl2 was removed by an evaporator. The crude product was purified by recrystallization (hexane/CHCl3). The target compound was obtained as a white solid (20.4 g) in 64% yield. 1H-NMR (400 MHz, CDCl3); delta=1.93 (dd, J=1.1, 1.2 Hz, 3H), 3.73 (td, J=5.4, 5.2 Hz, 2H), 4.35 (dd, J=5.1, 5.0 Hz, 2H), 5.63 (dq, J=1.4, 1.5 Hz, 1H), 6.12-6.14 (m, 1H), 7.09 (brs, 1H). 19F-NMR (376 MHz, CDCl3, C6F6 as standard); delta=40.68 (t, J=5.1 Hz, 1F), −105.91 (d, J=4.8 Hz, 2F).