Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]([Cl:20])([Cl:19])[CH:8]([NH2:18])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>CC(C)=O>[Cl:6][C:7]([Cl:19])([Cl:20])[CH:8]([NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:18][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (79g) in acetone (100 ml) was added dropwise to a solution of 1,1,1-trichloro-2-amino-2-(benzamido)ethane (170g) in acetone (500 ml) containing triethylamine (64.2g). The mixture was stirred for 2 hours. The reaction mixture was poured into water (750 ml). The solid was collected, washed with water and dried (195g). Recrystallisation from nitromethane (or dioxane) gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (156g, m.p. 210°-213°)
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8](O)[C:7]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:6]=2[S:5]1(=[O:19])=[O:18])[CH:2]=[CH2:3].[CH2:20]([N:22](CC)CC)[CH3:21].S([Cl:37])(C1C=CC(C)=CC=1)(=O)=O.C(N)C>O1CCCC1>[ClH:37].[CH2:1]([N:4]1[CH2:9][CH:8]([NH:22][CH2:20][CH3:21])[C:7]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:6]=2[S:5]1(=[O:19])=[O:18])[CH:2]=[CH2:3]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: CCN
Solvent: C1CCOC1
Product: C=CCN1CC(NCC)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Product: Cl
Temperature: -16 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
The product from Step C (1 g, 3 mmol) was dissolved in tetrahydrofuran (50 mL) containing triethylamine (1.7 mL, 12.0 mmol) and the solution was cooled to -16° C. Tosyl chloride (1.1 g, 6.0 mmol) was added and the mixture stirred for 18 h at room temperature after which time it was cooled to 0° C. and ethylamine (10 mL) was added. After heating at reflux for 1 h the solvent was evaporated and the residue dissolved in ethyl acetate (50 mL) and washed with 1N HCL (3×20 mL). The combined aqueous washes were basified (sodium bicarbonate) and extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate solution (3×15 mL) and brine (3×15 mL), dried (MgSO4) and evaporated to give the desired free base (620 mg) as a syrup. This material was dissolved in ethanol (5 mL) and IN ethanolic HCL (5 mL) was added. This solution was then concentrated to dryness to give the desired product as a light yellow solid (400 mg): mp 243°-245° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[N:5]=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C>O.[Fe]>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[N:5]=[CH:4][C:3]=1[NH2:11]
Reactant: COCCn1ncc([N+](=O)[O-])c1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COCCn1ncc(N)c1Cl
Temperature: 90 °C
Yield: 69 %

Procedure:
To a suspension of 5-chloro-1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1 equiv) and iron dust (3 equiv) in water (0.51 M) was added acetic acid (2.6 equiv). The mixture was heated to 90° C. for 1.5 h, then cooled to room temperature. The reaction was quenched by addition of solid sodium bicarbonate and treated with ethyl acetate with continuous stirring. The mixture was filtered and the solid was rinsed with ethyl acetate. The combined filtrate was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (69% yield) as a brown oil. MS (ESI) m/z 176 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-tert-butoxycarbonylaminobutoxy)-6-hydroxybenzoic acid methyl ester (1.5 g, 4.4 mmol) in DMF (20 mL) is added benzyl bromide (0.56 mL, 4.6 mmol) and K2CO3 (1.8 g, 13.0 mmol). The suspension is stirred at RT for 3 h then is poured into water and extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 1:1) to afford the title compound as a colorless liquid: 1H NMR (CDCl3) δ 7.38-7.19 (m, 6H), 6.57-6.51 (dd, J=8.34, 12.63 Hz, 2H), 5.10 (s, 1H), 4.60 (s, 1H), 4.00 (t, J=6.06 Hz, 2H), 3.88 (s, 3H), 3.18-3.13 (m, 2H), 1.81-1.75 (m, 2H), 1.66-1.59 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)=[CH:15][CH:16]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Yield: 109.3 %

Procedure:
Using analogous procedure as those described to prepare intermediate I-38b, 1H-Indole-3-carbaldehyde (10 g, 68.96 mmol) was reacted with 1-(chloromethyl)-4-methoxybenzene (11.26 mL, 82.75 mmol) and 60% NaH (5.5 g, 137.92 mmol) in DMF (140 mL) at room temperature for 1 hour to afford 20 g of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[N:19]([O-])=O.[Na+].[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[NH2:27].C([O-])(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:9]=[N:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:19][C:30]3[C:29]([CH3:31])=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=3[CH3:23])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=N[O-]
Reactant: Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: Cc1cc(C)cc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)cc(C)c1N=Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A 4 g (16.53 mmol) amount of 4-amino-4'-nitroazobenzene (Disperse Orange 3) was dissolved in ice-cooled acetic acid (100 mL) containing 8 mL of 98% sulfuriic acid. Sodium nitrite (1.48 g, 21.40 mmol) dissolved in a small amount of water (less than 2 mL) was added dropwise to the stirred solution. The reaction temperature was maintained at 5° C. After 6 h of stirring, 3,5-dimethylaniline (5.0 g, 41.30 mmol) in 10 mL of acetic acid was added followed by slow addition of sodium acetate (4.10 g, 50.0 mmol). The resulting red solution was stirred at 5° C. for an additional 16 h. A 10% sodium hydroxide solution was slowly added to neutralize the reaction mixture. The precipitates formed were collected by filtration, washed with water several times, dissolved in THF, and dried over magnesium sulfate. Solvent was evaporated, and a dark red powder was obtained by precipitation in n-hexane. The solid was further purified by column chromatography (silica gel; THF: n-hexane=4 6), affording 3.51 g (61%) of 4-[4'-(4"-nitrophenylazo)phenylazo]-3,5-dimethylaniline as a dark red solid product.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](/[F:32])\[CH2:25][CH:26]1SCCCS1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+:39](C)C.CC(C)=O.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl.O>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:32])[CH2:25][CH:26]=[O:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCCC/C=C(/F)CC1SCCCS1)(c1ccccc1)c1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCC=C(F)CC=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the dithialane prepared in 3F (0.424 g, 0.86 mmoles) in dry methylene chloride (4 ml) was added at room temperature trimethyloxonium tetrafluoroborate (0.125 g, 0.86 mmoles) and the mixture was stirred for 1 hr. Then a 9:1 mixture of acetone and water (2 ml) containing calcium carbonate (0.172 g, 1.72 mmoles) was added and the mixture was stirred overnight at room temperature. The precipitate was filtered off and after dilution with saturated brine the mixture was extracted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the expected aldehyde as an oil which was used after drying under high vacuum (0.366 g, 92%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[N:1]1([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Under nitrogen atmosphere, a solution of pyrazole (743 mg) in DMF (10 mL) was cooled to 0° C., and thereto was added NaH (480 mg, 60%). The mixture was stirred at 0° C. for 10 minutes, and stirred at room temperature for one hour. Methyl 4-(bromomethyl)benzoate (2.50 g) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. To the mixture was added ice water (50 mL), and extracted three times with ethyl acetate-toluene, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=10/1→3/1) to give methyl 4-(1H-pyrazol-1-ylmethyl)benzoate (2.17 g, 92%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:19][C:20]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1([F:25])[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: FC1(F)CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(F)(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 47.3 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.3 g, 1.74 mmol) in DMF (2 mL) was added K2CO3 (0.72 g, 5.23 mmol) followed by 3,3-difluoropyrrolidine hydrochloride (0.74 g, 5.23 mmol) and the reaction mixture was heated for 4 h at 80° C. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.2 g, 47%). LCMS (ES+) 244.05 (M+H)+, RT 3.028 minutes (method 1).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:10]1C=CC=CC=1.[C:16](Cl)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[C:16]([NH:10][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:9])[CH3:1])=[CH:4][CH:5]=1)=[O:22])[CH3:21]
Reactant: CN(C)c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N, dimethyl aniline (5.3 mmole) was dissolved in dichloromethane (20 ml). To this solution was added, pyridine (0.86 ml) and stirred at 0° C. Ethyl chlorooxalate (5.6 mmole) dissolved in dichloromethane (5 ml) was added slowly at 0° C. The reaction mixture was stirred at room temperature for 1 h, concentrated to dryness diluted with water, extracted with dichloromethane, washed with saturated brine and dried oven Na2SO4. Concentrate to gave the N-(4-Dimethylamino-phenyl)-oxalamic acid ethyl ester, which was used for the next step.
Reaction SMILES: C1(C[O:8][CH2:9][C@H:10]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:20]([O:21]CC3C=CC=CC=3)[C@@H:11]2[O:12]CC2C=CC=CC=2)C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH2:31]([OH:32])[C@H:29]1[O:30][C@H:10]([CH2:9][OH:8])[C@@H:11]([OH:12])[C@@H:20]1[OH:21]
Reactant: OC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart E, 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 is reacted with lithium aluminum hydride in ether at reflux temperature under argon, giving 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-mannitol 38. Compound 38 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 2,5-anhydro-D-mannitol 39, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving the product of Formula I where R', R",R'" and R"" are phenyl, 2,5-anhydro-D-mannitol, 1,6-bis(diphenyl phosphate) 40. Compound 40 is hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R",R'" and R"" are hydrogen, 2,5-anhydro-D-mannitol, 1,6-bis(dihydrogen phosphate) 41. Compounds 40 and 41 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. Substituting other phosphorylating agents in the reaction from 39 to 40, as described in Flowchart A, will result in the corresponding tetraesters and mixed tetraesters. ##STR18##
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9]CC)=O)=[N:4][O:5][CH:6]=1.[Na].[CH3:13]O.[C:15]([O:18][CH3:19])(=[O:17])[CH3:16]>>[CH3:1][C:2]1[C:3]([C:7](=[O:9])[CH2:16][C:15]([O:18][CH2:19][CH3:13])=[O:17])=[N:4][O:5][CH:6]=1
Reactant: CO
Reactant: COC(C)=O
Reactant: CCOC(=O)c1nocc1C
Agent: [Na]
Product: CCOC(=O)CC(=O)c1nocc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.8 g of 2B in 5.4 ml of methyl acetate was added to 1 g of sodium hyride, and the mixture was heated at reflux for 7 hours, then 0.25 ml of methanol was added. When gas evolution ended, the mixture was heated at reflux for 15 minutes, then cooled and stirred at room temperature overnight. The mixture was quenched in water, the resulting mixture was acidified with glacial acetic acid, and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent. The residue was chromatographed on silica gel with a 1:3 v:v mixture of ethyl acetate and hexane as eluent. The middle fractions that were obtained gave ethyl 3-(4-methyl-3-isoxazolyl)-3-oxopropionate (2C), as a light yellow oil. 27 g of sodium methoxide was dissolved in a mixture of 100 ml of methanol and 100 ml of THF. 50 grams of aluminum oxide (activated, neutral, Brockmann I, Aldrich) was added and the mixture was stirred for 30 minutes. The solvents were removed under reduced pressure to give aluminum oxide-supported sodium-methoxide (2D).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:32]=3[N:31]=[C:30]2[CH:40]([F:42])[F:41])[N:18]=1.N>C1COCC1.O.C(O)(=O)C>[F:42][CH:40]([F:41])[C:30]1[N:29]([C:19]2[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=[C:17]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:18]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:32]=2[N:31]=1
Reactant: Nc1cccnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: N
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Yield: 72.6 %

Procedure:
To a solution of 3-aminopyridine (1.88 g, 20 mmol) in 100 mL THF was added LDA (10 mL, 2 M in THF; 20 mmol) and to the resulting suspension was added 1.99 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole at room temperature. After 5 min. the reaction was neutralized with acetic acid and diluted with water. After the pH was made slightly alkaline with aq. NH3, the precipitate was collected, washed with hot water, and dried. Recrystallization from EtOH (using CH2Cl2 to aid initial solubility) gave 1.65 g (73% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp 221-223° C.; 1H NMR (CDCl3) δ 8.86 (br, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.48 (br t, JHF=53.6 Hz, 1H), 7.35-7.31 (m, 2H), 7.22 (m, exchangeable with D2O, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.04 (s, 3H), 3.92 (m, 4H), 3.81 (m, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.4%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]3[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-morpholin-4-yl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M170) (336 mg, 0.575 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (155 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([Br:12])=[CH:4][CH:3]=1
Reactant: Cc1nc2c(N)cccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nc2c(N)ccc(Br)c2o1
Temperature: -5 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
Compound 474B (3.90 g, 26.3 mmol) was dissolved in DMF (45 mL) and cooled to −5° C. and N-bromosuccinimide (4.68 g, 26.3 mmol) was added in small portions and the reaction stirred for 5 h. The mixture was poured into 150 mL of ice water to give a cream colored solid which was filtered, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel eluting with 20% ether/CH2Cl2 gave compound 474C (3.36 g, 56%) as a beige solid. HPLC: 95.4% at 2.583 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 228.03 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>C1COCC1>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCO)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 72 h
Yield: 34.2 %

Procedure:
To a suspension stirred under argon at room temperature of 4-nitrobenzyl chloroformate (5 g, 23 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (25 mL) was added 3-amino-1-propanol (1.9 mL, 26 mmol). The resulting mixture was stirred for 72 hr. then was concentrated. The residue was purified by chromatography on silica gel (0.5-2% MeOH/CH2Cl2) to give the title compound (2 g, 34%) as a pale yellow oil: MS (ES) 255.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4]C=[C:2]1CC(O)=O.ClC[O:12][CH2:13][CH2:14][N+:15]([O-:17])=[O:16].[O:18]1CCCC1>N1C=CC=CC=1>[C:5]([S:1][CH2:2][O:12][CH2:13][CH2:14][N+:15]([O-:17])=[O:16])(=[O:18])[CH3:4]
Reactant: O=C(O)Cc1cccs1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])CCOCCl
Solvent: c1ccncc1
Product: CC(=O)SCOCC[N+](=O)[O-]

Procedure:
Thiolacetic acid (22.8 grams) and 41.7 grams of 2-chloromethoxy-1-nitroethane were mixed into 100 cc of tetrahydrofuran at room temperature and the clear solution was heated at reflux for 2 hours. The solution was cooled and 25 grams of pyridine was added. After an additional period of two hours at reflux the mixture was filtered and the solvent was removed from the filtrate by flash evaporation. The residue was taken up in ether, washed with 5 percent aqueous hydrochloric acid and water, dried over magnesium sulfate and the solvent again evaporated. Distillation in vacuo afforded 24.7 g of 2-acetylthiomethoxy-1-nitroethane, bp 106°-109° (0.2-0.5 mm); structure was confirmed by spectral analysis.
Reaction SMILES: [CH:1]1([CH:4]2[O:15][C:8]3[N:9]=[C:10]([Cl:14])[N:11]=[C:12](Cl)[C:7]=3[O:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[Cl:14][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:7]2[O:6][CH2:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[O:15][C:8]=2[N:9]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)OC(C1CC1)CO2
Solvent: CCN(CC)CC
Product: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Temperature: 140 °C
Yield: 82.3 %

Procedure:
A mixture of 7-cyclopropyl-2,4-dichloro-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (93 mg, 0.40 mmol), morpholine (150 μL, 1.71 mmol) and triethylamine (80 μL, 0.57 mmol) in IMS (3 mL) was heated at 140° C. for 35 minutes using microwave irradiation before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0-20% ethyl acetate in cyclohexane) affording 2-Chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (98 mg, 87%). LCMS: RT=3.02 min, [M+H]+=284/286.