Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Reactant: NC1CCCC1
Solvent: CO
Product: O=S1(=O)N(CCOCCNC2CCCC2)c2ccccc2N1c1c(F)cccc1F

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with cyclopentylamine (2.4 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)cyclopentanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white soldi (0.94 g, 87%). HRMS: calcd for C21H25F2N3O3S+H+, 438.16574; found (ESI, [M+H]+Obs'd), 438.1652.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:15][N:16]=1>O.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:14]2[S:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=2)[CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Add a solution of sodium hydroxide (2.60 g, 65 mmol) in water (50 mL) to a solution of 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (5.76 g, 16 mmol) in methanol (100 mL) at 0° C. under nitrogen, warm the mixture to room temperature, and stir for a total of 1.5 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate by filtration to afford 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid (5.21 g, 95%): APCI mass spectrum m/z 338 [C16H18ClNO3S—H]−.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](Br)[CH3:19].[H-].[Na+]>CN(C)C=O>[CH:18]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)([CH3:19])[CH3:17]
Reactant: CC(C)Br
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2ccccc2Oc2ccccc21
Yield: 37 %

Procedure:
Following the proceedure described in Example 1, 3.0 grams of 10H-dibenz[b,f][1,4]oxazepin-11-one and 3.7 grams of 2-propyl bromide were reacted in the presence of 0.82 grams of a 50% dispersion of sodium hydride in mineral oil and 50 ml of dry dimethylformamide. The product was purified on the silica gel column (ethyl acetate/hexane, 1:4). The resulting oil was dissolved in petroleum ether which on standing gave 1.33 grams (30% of theory) of 10-isopropyl-10H-dibenz[b,f][1,4]oxazepin-11-one as colorless needles, m.p. 102°-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:24][CH:25]=[C:26]([C:32](OCC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.O>CN(C)C=O>[O:24]=[C:25]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:32]=[C:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (4.4 g) and diethyl ethoxymethylenepropanedioate (5.5 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 3 hours. To the reaction mixture was added water. The resulting crystals were collected by filtration, washed with water, and suspended in dichloromethane under heating. After the suspension was cooled to ambient temperature, the resulting crystals were collected by filtration and washed with dichloromethane. There was obtained ethyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.4 g). The filtrate was concentrated to 1/4 of its original volume and cooled to 0° C. to yield an additional 0.37 g of the same product. The cryde substance (2.77 g) obtained above was chromatographed on silica gel with 2% methanoldichloromethane. The product was recrystallized from a mixture of methanol and dichloromethane to give crystalline pure product (2.45 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].[Cl:14][C:15]1[C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[N:19][CH:18]=[CH:17][N:16]=1>>[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][CH2:3][CH2:2][NH:1][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1)(=[O:8])[NH2:9]
Reactant: Clc1nccnc1OCC1CO1
Reactant: NCCOc1ccccc1C(N)=O
Product: NC(=O)c1ccccc1OCCNCC(O)COc1nccnc1Cl

Procedure:
Analogously to the process described in Example 23, 9.0 g of 2-(2-aminoethoxy)-benzamide and 9.3 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine give 1-[2-(2-carbamoylphenyloxy)-ethyl-amino]-3-(2-chloro-3-pyrazinyloxy)-2-propanol, melting point 132°-133° C. The neutral fumaric acid salt prepared therefrom using the calculated amount of fumaric acid crystallises from a mixture of methanol and diethyl ether, melting point 167°-168° C.
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>C(O)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[N:17][NH:16][C:14]([C:13]1[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:15]
Reactant: NNC(=O)c1cccnc1Oc1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Oc1ccccc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 2-phenoxypyridine-3-carboxylic acid hydrazide (913 mg, 4 mmol), 3-trifluoromethylbenzaldehyde (696 mg, 4 mmol) in ethanol (40 mL) was refluxed for 13 h. It was cooled to room temperature and some precipitate was observed. The mixture was diluted by water (40 mL) and the solid was collected by filtration and washed with ethanol/water (1:1), dried to give 1.41 g (92%) of the title compound. 1H NMR (CDCl3): 10.84 (s, 1H), 8.63 (m, 1H), 8.23 (s, 1H), 8.16 (m, 1H), 7.91 (bs, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.40 (m, 3H), 7.24 (t, J=7.2 Hz, 1H), 7.18–7.08 (m, 3H).
Reaction SMILES: F[C:2]([F:20])(F)[C:3](=[N:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4]#[C:5][C:6]([O:8][CH3:9])=[O:7].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:3]2[C:2]([F:20])=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:27]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)C#CC(=Nc1ccc(OC)cc1)C(F)(F)F
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
In a typical reaction, methyl 5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate is mixed with about a 2.5 to 3 fold excess of 4-chlorobenzyl amine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous terahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude methyl 4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:3])[CH3:2].[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:34](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([F:37])=[C:28]([Br:27])[N:33]=2)[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC(=O)O[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following Method 9, (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (1R,2R,4R,6S)-4-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate was obtained. LCMS (m/z): 567.2 (MH+), Rt=0.82 min.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([NH:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C[C@@H](CO)NCc2ccccc2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl)benzamide (207 mg) and benzaldehyde (106 mg) in 1,4-dioxane (5 ml) was refluxed for 3 hours, and the mixture was evaporated in vacuo. To the residue in methanol (5 ml) was added sodium borohydride (15 mg) on ice-cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (S)-N-[4-[2-(benzylamino)-3-hydroxypropyl]phenyl]benzamide (250 mg) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]
Reactant: CCCOC(=O)Cl
Reactant: Nc1ccc(NCc2cc(Cl)cc(Cl)c2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCCOC(=O)Nc1ccc(NCc2cc(Cl)cc(Cl)c2)cc1N
Yield: 58.7 %

Procedure:
A suspension of 15.5 g (50 mmol) 2-amino-5-(3,5-dichlorobenzylamino)-nitrobenzene is hydrogenated in a manner analogous with Example 1 (variant A) and worked up appropriately with 6.2 g (51 mmol) propyl chloroformate. 10.8 g of the end product are obtained in the form of the dihydrochloride. This forms colorless to pale pink crystals.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:61])([CH3:60])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:49][CH2:48]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][O:31][CH2:30][CH2:29][N:28]4C(OC(C)(C)C)=O)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1>FC(F)(F)C(O)=O.ClCCl>[Cl:68][C:65]1[CH:66]=[CH:67][C:62]([C:55]2[CH2:56][C:57]([CH3:60])([CH3:61])[CH2:58][CH2:59][C:54]=2[CH2:53][N:50]2[CH2:51][CH2:52][N:47]([C:45]3[CH:44]=[CH:43][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:32][O:31][CH2:30][CH2:29][NH:28]5)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:46]=3)[CH2:48][CH2:49]2)=[CH:63][CH:64]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5COCCN5C(=O)OC(C)(C)C)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5COCCN5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A solution of EXAMPLE 66B in 50% trifluoroacetic acid and dichloromethane mixture was stirred at ambient temperature for 2 hours. The solvents were evaporated and the residue was purified on a reverse phase HPLC using a gradient of 20-80% acetonitrile in water containing 10 mM ammonium acetate. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.61 (s, 1H), 8.52 (bs, 1H), 8.49 (d, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (dd, 1H), 6.34 (s, 1H), 6.21 (d, 1H), 3.89 (d, 1H), 3.76 (d, 1H), 3.55-3.46 (m, 2H), 3.40-3.35 (m, 4H), 3.04 (m, 4H), 2.91 (t, 1H), 2.73 (s, 2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[CH:35]=O.O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43]
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCOc1ccc(C=O)cc1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(/C=C/CCO)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
n-Butyllithium (1.6 M in hexane, 25 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.03 g) in dry THF (50 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 10 min and then 3methoxy-4-(methoxymethoxy)benzaldehyde (3.60 g) in dry THF (10 ml) was added dropwise over 5 min. The mixture was allowed to warm to room temperature, stirred for 4 h water (10 ml) was added and the majority of the solvent was removed in vacuo at 40°. A solution of the residual oil in ER (200 ml) was washed with water (150 ml), dried, treated with charcoal, concentrated and purified by [FCS] eluting with EA/hexane (1:1) to give the title compound (1.55 g). T.l.c. (EA-hexane 1:1) Rf 0.30.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:13][C:14]1([CH2:20][CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][S:2]([O:23][CH2:22][CH2:21][CH2:20][C:14]1([O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCO)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CCCOS(C)(=O)=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (2.1 mL, 27.4 mmol) was added dropwise to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol (6.80 g, 24.9 mmol) and triethylamine (4.20 mL, 29.9 mmol) in dichloromethane (100 mL) at 0° C. The solution was stirred for 2 h at 0° C., then was diluted with dichloromethane (20-25 mL) and saturated aqueous sodium bicarbonate (70 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl methanesulfonate as a pale oil that was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:19])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:22])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(N1CCc2cc(O)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
1.30 g (4.27 mmol) of 2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone are dissolved in 20 ml DMF. At room temperature 0.59 g (4.27 mmol) potassium carbonate and 0.26 ml (4.27 mmol) methyliodide are added and the mixture is stirred overnight. Then it is filtered and the filtrate is concentrated by evaporation i.vac., the residue is triturated with water and suction filtered and dried in the circulating air dryer at 45° C.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]2[CH2:33][O:32]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[OH:32][CH:31]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:33][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(C2CO2)ccc1C#N
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCSCc1cccnn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]pyridazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyridazinylmethylthio)ethyl]guanidine. Similarly, by the procedure of Example 2(iii), there is obtained N-methyl-N'-nitro-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13](Cl)=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>ClCCl>[CH2:17]([NH:20][C:13](=[O:14])[C:4]1[C:3]([I:16])=[C:2]([NH2:1])[C:10]([I:11])=[C:6]([C:7]([NH:1][CH2:2][CH:10]=[CH2:6])=[O:8])[C:5]=1[I:12])[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: ClCCl
Product: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of 5-Amino-2,4,6-triiodo-isophthaloyl dichloride in dichloromethane was added allylamine (4 equivalents) under a nitrogen atmosphere at ambient temperature. The reaction was stirred for 18 hours. This yielded a precipitate which was found to be the desired product. 1H NMR (DMSOd6) 8.62 (2H, t, j 4.5 Hz), 5.90 (2H, m), 5.46 (2H, br s), 5.37 (2H, d, j 9 Hz), 5.14 (2H, d, 6 Hz), 3.84 (4H, t, 3 Hz). 13C (DMSOd6) 169.6, 149.0, 147.4, 116.0, 79.7, 41.5.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:8]([F:11])([F:10])[F:9])(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.O>[N:23]([CH2:6][CH:7]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([F:11])([F:10])[F:9])=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate (213 g, 625 mmol) in DMF (2500 mL) was added sodium azide (91.1 g, 1.40 mol). The reaction mixture was heated to 80° C. After 16 hours, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (3×500 mL). The organics were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to afford benzyl (3-azido-1,1,1-trifluoropropan-2-yl)carbamate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.B>CO>[C:34]1([CH2:33][NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]2[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[N:22]=2)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:8])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reactant: O=Cc1ccccc1
Agent: B
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(N(CCCNCc2ccccc2)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reaction time: 0.25 h

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (50 mg, 0.11 mmol) (a compound of formula (Yc6)) in methanol (2 mL) was added benzaldehyde (0.2 M in methanol, 68 μL, 0.14 mmol). After stirring for 15 minutes, borane-pyridine complex (0.2 M in methanol, 0.14 mmol) was added. After 2 hours, the solution was evaporated. The residue was partitioned into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (2:1 ethyl acetate/hexanes) to provide 2-[[3-(phenylmethylamino)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc8); as a white solid; NMR (CDCl3) 8.65 (s, 1), 7.7 (s, 1), 7.2 (br, 5), 7.1 (s, 1), 6.6 (d, 1), 6.55 (s, 1), 6.5 (d, 1), 6.1 (br, 2), 5.9 (s, 2), 3.95 (br, 6), 2.7 (m, 3), 2.35 (s, 6) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:13](=O)[CH2:14][CH3:15]>>[CH:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[CH:14][CH3:15]
Reactant: C1COCCN1
Reactant: CCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=CN1CCOCC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A reaction flask was charged with morpholine (938 g, 10.8 mol) and potassium carbonate (K2CO3) (800 g, 5.8 mol) and heated to 40° C. with stirring. Propionaldehyde (500 g, 8.6 mol) was added dropwise while the temperature was kept under 60° C. with a water bath. After the completion of the addition, the reaction mixture was aged for two hours and filtered. The obtained filtrate was further distilled to provide 4-propenyl-morpholine (850 g, 6.7 mol).