Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.N1C=CC=CC=1.[Cl:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].Cl>O.C(OCC)(=O)C>[Cl:13][C:3]1[C:2]([NH:1][S:22]([CH2:21][Cl:20])(=[O:24])=[O:23])=[CH:7][C:6]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([F:12])[CH:4]=1
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(=O)Nc1cc(N)c(Cl)cc1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 20 °C

Procedure:
1000 g of crude N-(5-amino4-chloro-2-fluorophenyl)acetamide (4.93 mol) which still contained 1 L of ethyl acetate was dissolved in 3900 g (49.3 mol) of pyridine at 20° C. To the yellow solution was added 845 g (5.42 mol) of chloromethanesulfonyl chloride at 20-30° C. over 1-2 hours. The solution was allowed to stir for 1 additional hour. 2300 g of pyridine were distilled off under reduced pressure at 40° C. To the remaining reaction mixture were added 5.3 L of water and 1.7 L of concentrated HCl (pH 3) whereupon the product precipitated. The slurry was cooled to 20° C. and filtered off. The filter cake was washed twice with 1300 mL of water. The product was dried in vacuo at 70° C. to yield 1500 g (92% purity) of the title compound as a solid melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[CH:9]=[O:10].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[CH2:9][OH:10]
Reactant: COC(=O)COC/C=C/C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COC/C=C/CO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59.4 %

Procedure:
To a solution of 311 mg of 2-[3-formyl-(E)-2-propen-1-yloxy]acetic acid methyl ester in 10 ml of methanol, 149 mg of sodium borohydride was added, followed by stirring at room temperature for 4.5 hours. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate after adding ice water. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 187 mg of the desired crude product as an oily substance.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([O:14]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10.0 g (0.04 mol) of methyl 3-benzyloxyimino-2-oxovalerate and 20 ml of morpholine were combined and the mixture was stirred for 3 hours at 100° C. After distilling the morpholine off under reduced pressure, 100 ml of water was added and the mixture was extracted three times with 100 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 6.78 g (yield: 56%) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine as a white solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[S:12]1[CH2:17][CH2:16][CH:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: OC1CCSCC1
Product: CCOC(=O)/C(=N\OC1CCSCC1)C(C)=O
Yield: 20 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (5.72 g) was reacted with tetrahydro-4H-thiopyran-4-ol as described in Example 4a. method 3 to give the title compound (1.82 g, 20%) as colourless liquid, νmax (film) 2930, 1740, and 1690 cm-1, δH (CDCl3) 1.35 (3H, t), 2.06 (2H,m), 2.21 (2H, m) 2.40 (3H, s), 2.57 (2H, m), 2.82 (2H, m), and 4.37 (3H, q+m), δc (CDCl3) 14.2, 25.2, 25.3 (2C), 32.1 (2C), 62.0, 81.9, 150.5, 161.2 and 192.7. [Mass spectrum, MH+ (260)].
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-dichlorobenzhydrol (1.14 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.76 g (yield: 83%-) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:4][C@@H:3]1[OH:10].[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:18][CH:19]([C:27](=[O:28])[NH:1][CH:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:4][CH:3]1[OH:10])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: N[C@@H]1c2ccsc2C[C@@H]1O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the racemic cis-4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-5-ol (17.5 g, 0.112 mol) in dry DMF (400 mL) was added Boc-L-phenylalanin (30.51 g, 0.115 mol) HOBT (15.6 g, 0.115 mol) and EDAC (22.0 g, 0.115 mol). To the stirred mixture was added TEA (16 mL, 0.115 mol) and the mixture was stirred at room temperature overnight. The mixture was added to 5% citric acid and extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogen carbonate (two times). The organic phase was dried with sodium sulphate and evaporated under reduced pressure. Yield: 43 g=95%
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>O1CCCC1>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:23](=[O:24])[CH2:22][C:21](=[O:25])[CH3:20])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)N1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 g (0.1 mol) of 1-cyclohexylpiperazine are suspended in 150 ml of absolute tetrahydrofuran. 20 ml of triethylamine are poured in and, after 20 minutes, 18.6 g of diketene in 20 ml of tetrahydrofuran are added dropwise, and the mixture is then stirred at room temperature for 2 h. Thereafter part of the solvent is removed by distillation in vacuo, the mixture is poured onto 200 ml of ice-water, 20 g of Na2CO3 are added, and extraction is carried out 3 times with 50 ml of methylene chloride each time. After the organic phase has been dried with MgSO4, crude 3-oxo-butyric acid 4-cyclohexylpiperazide is obtained as the residue from evaporation.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]([OH:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C(C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccnc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 1-(3-methyl-pyridin-2-yl)-ethanol (330 mg, 2.41 mmol) (Kawasaki et al. Nippon Kagaku Zasshi 1962, 83, 949) and NEt3 (0.50 mL, 3.6 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. under N2. MsCl (0.22 mL, 2.8 mmol) was added and the reaction was stirred at 0° C. for 15 minutes. The reaction was diluted with saturated aqueous NaHCO3 (10 mL), the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure, giving the crude methanesulfonic acid 1-(3-methyl-pyridin-2-yl)-ethyl ester as an orange oil (484 mg, 2.25 mmol, 93%). 1H NMR (CDCl3) δ 1.76 (d, 3H, J=6.6 Hz), 2.45 (s, 3H), 2.84 (s, 3H), 6.07 (q, 1H, J=6.6 Hz), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (dd, 1H, J=7.8, 0.9 Hz), 8.51 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][CH2:10][CH:11]([OH:13])[CH3:12].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:13][CH:11]([CH3:12])[CH2:10][F:9]
Reactant: Clc1ccncc1Br
Reactant: CC(O)CF
Agent: [H-]
Agent: [Na+]
Product: CC(CF)Oc1ccncc1Br

Procedure:
The title compound was synthesized in analogy to Example 108b, using 3-bromo-4-chloropyridine (CAN 36953-42-1), 1-fluoropropan-2-ol (CAN 430-50-2) as starting materials and sodium hydride as reagent. The title compound was isolated (7.55 g, 62%) as a yellow oil; MS (ESI, m/z): 235.9 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[OH-].[K+]>CO.C(OCC)(=O)C.[Ni]>[OH:16][C:14]1[C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:7]2[C:8](=[O:11])[N:9]3[CH:10]=[CH:2][CH:3]=[C:4]3[O:5][C:6]=2[CH:15]=1
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(O)cc2oc3cccn3c(=O)c2c1O
Yield: 36.4 %

Procedure:
A solution of 60 mg (0.18 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 4 mL of methanol was subjected to hydrogenation with 0.1 g Ra-Ni, 0.4 mL of 0.5N KOH in methanol, and H2 at 20 psi. The mixture was diluted with ethyl acetate and extracted with 1N HCl. The organic layer was dried (Na2SO4), concentrated, and the residue purified by preparative TLC (Silica Gel: CH2C2) to give 17 mg of the title compound: mp 170-171° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Br.C1(O)C=CC=CC=1>O1CCCC1.O>[O:25]1[CH2:24][CH:23]1[CH2:21][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: BrCC1CO1
Reactant: CN1Cc2cc(O)ccc2C(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CN1Cc2cc(OCC3CO3)ccc2C(c2ccccc2)C1

Procedure:
Sodium hydride (0.72g) was added to a solution of 7-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (2.33g) in dry tetrahydrofuran (75 ml). Epibromohydrin (4.11 g) was added and the solution refluxed for 2 hr. until thin layer chromatography (alumina, chloroform-ether 1:5) showed the absence of starting phenol. Water (25ml) was added and the mixture extracted with ether. The combined ether layers were dried (MgSO4) and the solvent removed under reduced pressure. The oil was taken up in xylene (50 ml) and evaporated to dryness to give the title compound in quantitative yield. τ (CDCl3) 7.68 (3H,s), 7.55-7.0 (3H,m), 6.95-6.6 (2H,m), 6.4 (2H,s), 6.2-5.65 (3H,m), 3.5-3.1 (3H,m), 2.85 (5H,s).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].CO>C(Cl)Cl.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>[O:21]=[C:18]1[NH:8][CH:7]=[C:6]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:5]=[CH:4]1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 90 °C
Yield: 117.1 %

Procedure:
IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl 4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boronoic acid (25.0 g, 163 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO4) and concentrated to give a brown solid. The crude residue was subject to column chromatography (0 to 1.5% MeOH in DCM) to give a white solid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (20.95 g, 63.8 mmol, 58% yield).
Reaction SMILES: [CH3:1][Mg]I.[CH2:4]([O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C:18](=[CH:19][CH2:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C@H:15]1[OH:28])[CH3:5].[NH4+].[Cl-]>C(OCC)C>[CH2:4]([O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C:18](=[CH:19][CH2:20][C:21]([OH:27])([CH3:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C@H:15]1[OH:28])[CH3:5]
Reactant: C[Mg]I
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(C)(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl magnesium iodide (prepared from 816 mg. magnesium filings and 2.12 ml. methyl iodide) dissolved in 80 ml. dry diethyl ether is added dropwise to 3.9 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 200 ml. dry diethyl ether, with the exclusion of moisture, under nitrogen and with stirring. The mixture is stirred for 15 minutes more at room temperature and mixed dropwise, with ice cooling, with 300 ml. saturated aqueous NH4Cl solution. The organic phase is separated, washed with water and dried over Na2SO4. The solvent is removed by distillation to yield as residue 9β,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester, which is separated chromatographically (first silica gel/dichloromethane:acetone = 10:1; then silica gel/petroleum ether:ethanol = 9:1) into the two 15-epimers;
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]=[S:14])[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][NH:18][C:13](=[S:14])[NH:12][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:3]=1[CH2:1][CH3:2]
Reactant: NCCN
Reactant: CCc1c(N=C=S)ccc2ocnc12
Solvent: Cc1ccccc1
Product: CCc1c(NC(=S)NCCN)ccc2ocnc12
Reaction time: 0.5 h

Procedure:
A solution of 4-ethyl-5-isothiocyanatobenzoxazole (3.58 mmol) in toluene (75 mL) is treated with ethylenediamine (12.53 mmol). The reaction is stirred for 30 minutes as the product precipitates. The precipitate is filtered and dried in an oven to yield 5-[N'-(2-aminoethyl)thioureido]-4-ethylbenzoxazole as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1>C(O)C>[CH:16]1([CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:18][CH2:17]1
Reactant: NCC1CC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
Following general procedure 2B: To methyl 4-fluoro-3-nitrophenylcarbamate (6.50 g, 30.35 mmol, from previous step) in 80% aqueous ethanol (100 mL) was added cyclopropanemethylamine (5.00 mL, 57,65 mmol) at room temperature. The reaction mixture was heated at 60° C. overnight. After the usual work up, the crude product, which precipitated out, was collected (8.21 g). MS (ESI) (M+H)+=266.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[C:12]3[N:13]([C:15](Cl)=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.NC1CCC(NC2C=C(NC3C=CC(OCC)=CC=3)C3N(C(Cl)=C(Cl)N=3)N=2)CC1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOc1ccc(Nc2cc(NC3CCC(N)CC3)nn3c(Cl)cnc23)cc1
Agent: CCOc1ccc(Nc2cc(NC3CCC(N)CC3)nn3c(Cl)c(Cl)nc23)cc1
Product: CCOc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1

Procedure:
To a mixture of crude N6-(4-aminocyclohexyl)-2,3,7-trichloro-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine from if as a free base (140 mg, 0.300 mmol) in EtOH (10 ml) in a 500 ml PARR bottle was added 10% Palladium on carbon (175 mg). The PARR bottle was then charged with H2 at 55 psi and allow to shake at room temperature for 24 hours. The catalyst was then filtered and the filtrate was concentrated in vacuo to give a crude mixture of 3 compounds. This mixture was purified by preparative HPLC to give 4.7 mg of Example I(1), N6-(4-aminocyclohexyl)-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine as a TFA salt, LC/MS, m/e 367 (M+1). 9.0 mg of N6-(4-aminocyclohexyl)-3-chloro-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine, LC/MS, m/e 401 (M+1) and 18.5 mg of N6-(4-aminocyclohexyl)-2,3-dichloro-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine, LC/MS, m/e 435 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH2:25][NH:26][CH2:27][CH2:28][CH3:29].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([S:8][C:9]3[CH:10]=[C:11]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:4]=2)[N:1]=1
Reactant: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(Sc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N

Procedure:
A mixture of N-[3-(4-Amino-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0016 mol) and cyanogen bromide (0.0020 mol) in ethanol (q.s.) was reacted overnight at room temperature and then the organic solvent (EtOH) was evaporated. The obtained concentrate was warmed in EtOH and then cooled. The mixture was filtered and the collected residue was recrystallized from EtOH to yield the title compound as a solid.
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6].C([O:11][C:12](=O)[CH:13]([CH2:17][CH3:18])[C:14]([CH3:16])=O)C.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:3]([C:2]1[NH:8][C:12](=[O:11])[C:13]([CH2:17][CH3:18])=[C:14]([CH3:16])[N:7]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)c(CC)c(=O)[nH]1

Procedure:
A solution of 3.0 g valeramidine hydrochloride, 3.47 g ethyl-2 ethylacetoacetate, and 5.8 mL triethylamine in 20 mL DMF was heated to 120° C. for 18 hours. The mixture was diluted with brine and extracted three times with ether. The combined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, and then was still flash chromatographed in 3% MeOH in CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].S(Cl)(Cl)=O.Br.Br.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([N:28]2[C:32]([CH3:33])=[N:31][N:30]=[C:29]2[CH2:34][NH2:35])[CH:22]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C)C=O.C1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([N:28]2[C:32]([CH3:33])=[N:31][N:30]=[C:29]2[CH2:34][NH:35][C:1](=[O:6])[C:2]([CH3:4])=[O:3])[CH:22]=1
Reactant: CC(=O)C(=O)O
Reactant: Cc1nnc(CN)n1-c1cc(Cl)cc(C(=O)c2ccccc2Cl)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)C(=O)NCc1nnc(C)n1-c1cc(Cl)cc(C(=O)c2ccccc2Cl)c1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A solution of pyruvic acid (0.33 g) and thionyl chloride (0.27 g) in chloroform (2 ml) is refluxed for 1 hour. After cooling, the solution is mixed with 2',5-dichloro-3-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (1.31 g), benzene (6 ml) and dimethylformamide (11 ml) at 0° C. The resultant mixture is stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water, dried and evaporatored to remove the solvent. The residue is recrystallized from ethyl acetate to give 2',5-dichloro-3-(3-pyruvamidomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone (0.7 g) as crystals melting at 178° to 180° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[CH3:29][C:30]1[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:36]([C:32]4[S:31][C:30]([CH3:29])=[N:34][C:33]=4[CH3:35])=[O:37])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (120 mg, 0.31 mmol) was dissolved in DMF (1.5 mL), and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (58 mg, 0.37 mmol) was added. PYBOP (193 mg, 0.37 mmol) and diisopropylethylamine (0.16 mL, 0.93 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (131 mg, 80%): HPLC MS RT=2.05 min, MH+=527.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 8.02 (1H, d), 7.43 (1H, d), 4.38 (2H, m), 4.32 (2H, m), 4.22 (2H, m), 4.00 (3H, s), 3.81 (2H, m), 3.53 (2H, d), 3.28 (2H, m), 2.72-2.63 (8H, m), 2.26 (2H, m), 1.13 (6H, d).