Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=C[CH:15]=1)#N.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:4]([N:22]2[CH2:21][CH2:20][C:19]([C:18]3[CH:15]=[CH:14][C:27]([C:28]#[N:29])=[CH:26][CH:17]=3)([OH:25])[CH2:24][CH2:23]2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2(O)CCN(C(=O)c3cccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A suspension of 2-chloronicotinic acid (0.20 g), 4-(4-cyanobenzyl)-4-hydroxypiperidine hydrochloride (0.32 g), HATU (0.72 g) and triethylamine (0.89 mL) in DMF (4.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and filtered through basic silica gel. The filtrate was concentrated under reduced pressure to give the title compound (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:26][CH2:27][O-:28].[Na+]>C(O)C>[CH2:27]([O:28][C:15]1[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:2]([Cl:1])=[C:3]([CH:9]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=1)[CH3:26]
Reactant: CCOC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using ethyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained ethyl 5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 94°-96° C.;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=Cc2cccnc2N)C=C1

Procedure:
A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanouacetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH2:22])[N:18]=2)[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2CO3 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80° C. for 30 h. Then the reaction was cooled to RT. EtOAc was added and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].Br[CH2:25][CH:26]([OH:30])[CH2:27][CH2:28]Br>>[OH:30][CH:26]1[CH2:27][CH2:28][N:1]([CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:25]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: OC(CBr)CCBr
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(O)C1

Procedure:
The title compound, colorless gum, MS: m/e=419.2 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and 1,4-dibromo-2-butanol.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH:21][S:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Phenylmethanesulfonyl chloride (10.5 g, 55 mmol) was added into a solution of (R)-1-(4-bromophenyl)ethanamine (10 g, 50 mmol) in pyridine (100 mL) drop wise at 0° C. The reaction mixture was stirred at 10° C. for 1 hour. The reaction was poured into water (500 mL), the pH value adjusted to 5 with 6 N aqueous HCl, extracted with EtOAc (100 mL×4). The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound (13 g, 73% yield) as pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]1[O:10][CH:8]1[CH3:9]>>[OH:10][CH:8]([CH3:9])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC1CO1
Product: CC(O)CN1CCOCC1
Reaction time: 168 h
Yield: 96.1 %

Procedure:
An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=C([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])CN.NC1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1>[OH-].[Na+]>[CH3:26][O:25][C:21]1[CH:20]=[C:10]([CH:16]=[C:15]([O:14][CH3:13])[C:22]=1[O:23][CH3:24])[CH2:9][NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CNC(=O)NCc2ccc(C(=O)O)cc2)cc(OC)c1OC
Yield: 94.6 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), 3,4,5-trimethoxybenzyl amine (1.97 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide are used according to the method for the production of compound III in Method two to obtain 3.54 g of 4-[(3,4,5-trimethoxybenzylureido)methyl]benzoic acid (intermediate M-35) as a white solid, with a yield of 94.6%.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:17])[C:13](OC)=[O:14])[C:5](OC)=[O:6].C(O)CCCC>C(N(CC)CC)C>[CH:12]12[NH:17][C:5](=[O:6])[CH:4]([NH:3][C:13]1=[O:14])[CH2:9][CH2:10][CH2:11]2
Reactant: COC(=O)C(N)CCCC(N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: O=C1NC2CCCC1NC2=O
Yield: 69.3 %

Procedure:
A solution of 39.0 g (0.134 M) of 2,6-diaminoheptanedioic acid, dimethyl ester, dihydrochloride, 56 ml (0.4 M) of triethylamine, and 3 L of 1-pentanol was heated under reflux for 4 days. The solution was evaporated to dryness and the residue was recrystallized from chloroform to give 14.3 g of the title compound, mp 280°-3° (69%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cccnc1
Product: CCOC(=O)c1ccc(C)c(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]=1[NH2:16])[CH3:2].Cl[C:19]([O:21][C:22](Cl)(Cl)Cl)=[O:20].[CH2:26](O)C.C(N(CC)CC)C>C(OCC)(=O)C>[C:19]([NH:16][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[C:10]([CH2:11][CH3:12])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:17])([O:21][CH2:22][CH3:26])=[O:20]
Reactant: CCOC(=O)c1c(N)cc([N+](=O)[O-])cc1CC
Reactant: CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)OCC

Procedure:
A solution of ethyl-2-amino-6-ethyl-4-nitro-benzoate (400 mg) in ethyl acetate (10 ml) was added dropwise to a solution of trichloromethyl chloroformate in ethylacetate (10 ml). A precipitate was formed immediately which dissolved on prolonged sitrring for 21/2 hours. A solution of ethanol (5 ml) and triethylamine (5 ml) was added. A yellowish precipitate was formed. After 1 hour the solution was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine solution, dried over magnesium sulfate and evaporated to a reddish oil. The material was further purified by column chromatography on silica gel (10% EtOAc:pet.ether) to give a solid material, m.p. 47°-48° C., IR: 1530, 1710, 1740, 1610 cm-1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[NH:26][C:27]([SH:30])=[N:28][CH:29]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:27]3[NH:28][CH:29]=[N:25][N:26]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ncn[nH]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 30 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (129 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2H-[1,2,4]triazole-3-thiol
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl>[CH3:11][O:10][C:3]1[C:2]([NH:1][C:14](=[O:15])[CH2:13][Cl:12])=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ncnc(OC)c1N
Solvent: ClCCl
Product: COc1ncnc(OC)c1NC(=O)CCl
Temperature: 25 °C

Procedure:
A sulphonation flask is charged with 310 g 5-amino-4,6-dimethoxypyrimidin and 3500 ml dry CH2Cl2. To this mixture is added, within 15 minutes, a solution of 248.6 g chloroacetyl chloride in 400 ml dry CH2Cl2. The reaction is exothermic, the temperature rises from 14° to 32° and a suspension is formed. The reaction mixture is heated under reflux for 2 hours, then cooled to ambient temperature and evaporated till dryness. The solid residue is suspended in 3 l ice water, the suspension adjusted at pH 7-8 with diluted NaOH, cooled to 5° and sucked-off. The precipitate is washed twice with 500 ml ice water and then dried in vacuum at 60° to give the title compound, m.p. 193°-195°.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]4[CH:24]=[C:23]([C:25]([OH:27])=O)[S:22][C:16]4=[CH:17][CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:47]([NH:54][CH2:55][CH2:56][NH2:57])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C(Cl)CCl>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[NH:54][CH2:55][CH2:56][NH:57][C:25]([C:23]1[S:22][C:16]2=[CH:17][CH:18]=[C:19]3[C:14]([N:13]=[C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:3])(=[O:4])[NH2:2])[CH:6]=4)[N:21]=[CH:20]3)=[C:15]2[CH:24]=1)=[O:27])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3ccc4sc(C(=O)O)cc4c3n2)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carboxylic acid (150 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol), N,N-diisopropylethylamine (73 mg, 0.56 mmol) and BOC-ethylenediamine (66 mg, 0.41 mmol) were dissolved in dry DMF (2 mL) and cooled in an ice-bath. EDC (79 mg, 0.41 mmol) was added in one portion and the resultant suspension was stirred overnight allowing the ice-bath to melt. The reaction was concentrated under reduced pressure, redissolved in isopropanol (˜10 mL) and water was added (˜5 mL). The precipitate formed was isolated by filtration and washed with water (1×5 mL), dilute NaHSO4 (1×5 mL), water (1×5 mL), saturated Na2CO3 (1×5 mL), water (1×5 mL), isopropanol (1×5 mL), diethyl ether (2×5 mL) and pentane (2×5 mL) giving an ochre powder (102 mg, 51% yield). MS (ES+) 543. δH (d6 DMSO) 1.2-1.5 (9H, s), 3.3-3.5 (4H, br m), 6.6 (0.1H, br s), 7.0 (0.9H, br s), 7.1-7.4 (2H, br s), 7.4-7.6 (2H, m), 7.8-8.0 (2H, m), 8.2 (1H, m), 8.6-9.0 (3H, br m), 9.4 (1H, s), 10.3-10.6 (1H, br s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1CCCCN1
Product: CC1CCCCN1C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 2-methyl-piperidine. MS (ESI): 440.4 (MH+).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.ClCCO.[OH-].[K+].[CH3:10][CH:11]([NH2:15])[CH:12]([CH3:14])[NH2:13]>CO>[OH:3][CH2:1][CH2:2][NH:13][CH:12]([CH3:14])[CH:11]([CH3:10])[NH2:15]
Reactant: CC(N)C(C)N
Reactant: C1CO1
Agent: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(N)C(C)NCCO

Procedure:
Ethylene oxide generated from 2-chloroethanol (36 g) and potassium hydroxide pellets (20 g) in methanol (60 ml) was reacted which 1,2-dimethylethylenediamine (22.6 g) in methanol (50 ml) at -15° C. to give N-(2-hydroxyethyl)-1,2-dimethylethylenediamine as a colourless liquid (m.p. 89°-91° C. at 1 mmHg).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(=O)(O)[O-].[Na+].[O:13]=[C:14]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][C@H:15]1[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C)C=O>[O:13]=[C:14]1[NH:20][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:17]([CH:18]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:19]2)[CH2:16][C@H:15]1[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: BrC1C=CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2C=CCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-Bromocyclohexene (7.06 g) and sodium bicarbonate (3.68 g) were added to a solution of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (6.08 g) in anhydrous N,N-dimethylformamide (50 ml), and the mixture was stirred at 50° C. for one hour. The reaction mixture was allowed to cool, ice-water was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure,the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3), to thereby obtain 7.84 g of the titled compound.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[CH2:47]([S:54](Cl)(=[O:56])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][S:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:56])=[O:55])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (80 mg, 0.153 mmol) in dichloromethane (4 mL) was added pyridine (24 μL, 0.307 mmol) followed by benzylsulfonyl chloride (32 mg, 0.169 mmol). The mixture was stirred at room temperature for 16 h and concentrated. The solvent was removed under reduced pressure and the crude was dissolved in methanol (4 mL) and acetic acid (1 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 5% MeOH/dichloromethane as an eluent at afford the desired product as a yellowish solid (52 mg, 0.120 mmol, 79%). 1H NMR: 3.16 (t, 2H, J=63.4 Hz), 4.28 (t, 2H, J=6.4 Hz), 4.36 (s, 2H), 6.92 (t, 1H, J=6.8 Hz), 7.02 (s, 1H), 7.11 (d, 3H, J=7.2 Hz), 7.19 (s, 2H), 7.28-7.31 (m, 5H), 7.41 (s, 1H), 7.62 (s, 1H), 8.04 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:17][C:18]1[O:19][C:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)c2ccccc2)o1
Reaction time: 0.5 h

Procedure:
Into a flask containing benzoyl chloride (206 g) and dichloromethane (2 L) was added aluminum chloride (200 g) while stirring. After 30 minutes at ambient temperature the flask was placed in a water bath and a condenser was connected through which 2-methylfuran (210 mL) was added dropwise over 30 minutes. The resulting mixture was stirred for 7 hours then carefully poured into cold water (3 L). The organic layer was collected, washed with water and concentrated to afford (5-methylfuran-2-yl)(phenyl)methanone as an oily product (220 g).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCc1ccc(O)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 4-(4-aminobutyl)phenol hydrobromide 6 (8.2 g, 33.5 mmol), phthalic anhydride 7 (5.0 g, 33.8 mmol), and triethylamine (4.6 mL, 33.5 mmol) in chloroform (50 mL) was stirred at reflux for 18 h, cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in acetic acid (50 mL) and stirred at 100° C. for 3 h. Solvent was evaporated and the resulting residue was purified by flash silica gel column chromatography eluting with CH2Cl2/EtOAc/hexanes (8:1:1, v/v) to give the desired product 8 as a white powder (4.1 g, 41% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 4H), 2.46 (m, 2H), 3.58 (m, 2H), 6.64 (d, 2H), 6.95 (d, 2H), 7.82 (m, 4H), 9.12 (s, 1H). m/z (ESI): 296 [C18H17NO3+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14].[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[OH:27]>C(O)(C)C>[OH:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[NH:21][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1)[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: Cc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: CC(C)O
Product: Cc1nc(N[C@@H]2CCC[C@H]2O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 22 h
Yield: 92.2 %

Procedure:
A mixture of 6-chloro-2-methyl-9-(β-D-ribofuranosyl)-9H-purine (902 mg), trans-2-aminocyclopentanol (404 mg), DEA (517 mg) and isopropanol (35 ml) was heated under reflux with stirring for 22 h under nitrogen. Additional trans-2-aminocyclopentanol (202 mg) and DEA (259 mg) were added and heating under reflux was maintained for a further 5 h. The cooled mixture was concentrated in vacuo and the residual foam (1.9 g) was purified by column chromatography on silica (Merck 9385, deactivated with triethylamine) eluting with System B (10:1) to give a solid (1.01 g). This was repurified by column chromatography on silica (Merck 9385) eluting with System B (10:1) to give the title compound (0.57 g), m.p. 188°-192°.