Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=O.[OH-].[Na+]>ClCCCl>[N:20]1[CH2:24][CH2:23][CH2:22][C:21]=1[N:20]1[CH2:24][CH2:23][CH:22]=[C:21]1[N:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1CCCN1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C1=C(N2c3ccccc3Sc3ccccc32)N(C2=NCCC2)CC1
Reaction time: 4 h
Yield: 17 %

Procedure:
Phosphorus oxychloride (38.3 g., 0.25 mole) in 50 ml. of 1,2-dichloroethane is added in one portion to a stirred mixture of phenothiazine (49.8 g., 0.25 mole) and 2-pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2-dichloroethane. The mixture is stirred for 4 hr. at room temperature, permitted to stand for a period of 15 hr. and then poured into a mixture of 200 ml. of 5N sodium hydroxide and 100 g. of crushed ice. The 1,2-dichloroethane layer is separated and the aqueous layer extracted with 100 ml. of additional 1,2-dichloroethane. The combined 1,2-dichloroethane fractions are sequentially extracted with 300 ml. of 1.5N hydrochloric acid and 200 ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydroxide and extracted repeatedly with chloroform. After drying over magnesium sulfate, the chloroform solution is concentrated and the residual material thus obtained stirred with 200 ml. of acetone to remove the acetone soluble 10-[2-(1-pyrrolinyl)]phenothiazine by-product and filtered. The filter cake is washed with additional acetone and dried providing 14.1 g. (17% yield) of 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE as the free base, m.p. 199°-201° C. The bis-pyrrolinyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200-250 ml. of anhydrous ether providing the hydrochloride salt. Crystallization of the hydrochloride salt from absolute ethanol-anhydrous ether affords analytically pure 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL PHENOTHIAZINE[HYDROCHLORIDE solvated with 1/5 mole of ethanol as an off white solid, m.p. 237°-239° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=423.1, tR (minutes, Method G)=2.58. [α]D20=+18.1 (c=5.22 mg/mL,CHCl3) And the corresponding enantiomer
Reaction SMILES: C(O)(C)C.[OH2:5].[NH4+:6].[OH-].C1C=[C:12]2[C:14]([C:16]([OH:20])(O)[C:17](=[O:18])[C:11]2=[CH:10]C=1)=O>>[CH2:10]1[NH:6][CH2:14][C@@H:16]([OH:20])[C@H:17]([OH:18])[C@H:11]1[CH2:12][OH:5]
Reactant: O
Reactant: [NH4+]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: [OH-]
Solvent: CC(C)O
Product: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Reaction time: 72 h

Procedure:
TLC was performed on the different fractions (silica gel, isopropanol:water:NH4OH (7:2:1) and detection was via imino sugar and ninhydrin spray. Fractions testing positive with the imino-sugar sprays were analyzed to determine purity, then combined and lyophilized for 72 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:31])[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:27])([F:28])[F:29])=[C:20]2[C:19]=1[OH:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1c(C(F)(F)F)ccnc1Cl
Product: CCOC(=O)c1oc2nccc(C(F)(F)F)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-(trifluoromethyl)nicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([F:16])([F:15])[C:4]([F:14])([F:13])[C:5]([F:12])([F:11])[C:6]([F:10])([F:9])[CH2:7][CH3:8].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I:25].C=C>>[F:1][C:2]([F:17])([F:18])[C:3]([F:15])([F:16])[C:4]([F:13])([F:14])[C:5]([F:11])([F:12])[C:6]([F:10])([F:9])[CH2:7][CH2:8][I:25]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C=C
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI

Procedure:
1,1,1,2,2,3,3,4,4,5,5-Undecafluoroheptane (CF3CF2CF2CF2CF2CH2CH3) may be prepared by reaction of 1,1,1,2,2,3,3,4,4,5,5-undecafluoro-5-iodo-pentane with ethylene to give 1,1,1,2,2,3,3,4,4,5,5-undecafluoro-7-iodo-heptane followed by zinc reduction in an acid such as HCl or acetic acid.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][OH:8])[C:3]([OH:5])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][CH:2]2[CH2:6][CH2:7][O:8][C:3]2=[O:5])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NC(CCO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1OCCC1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
(RS)-2-amino-4-hydroxybutanoic acid (2.0438 g) was dissolved in water (20 ml). The solution was cooled to 0° C., and potassium carbonate (5.217 g) and ethyl acetate (20 ml) were added. Then, p-chlorobenzenesulfonyl chloride (9.0536 g) and THF (2 ml) were added, and the whole was stirred overnight. After the reaction was completed, the ethyl acetate layer was separated. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were concentrated to give a crude product. The crude product was purified by silica gel column chromatography (silica gel 50 g, hexane/ethyl acetate=2/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-4-butanolide (2.8674 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH2:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16].[CH3:20]N(C)N.C>CO>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:20]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CSC(C)(C)C
Reactant: CN(C)N
Agent: C
Solvent: CO
Product: CCOC(=O)c1ccc(N)cc1CSC(C)(C)C
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
2-tert-Butylsulfanylmethyl-4-nitro-benzoic acid methyl ester (5.68 g, 19.1 mmol), 1,1-dimethylhydrazine (11.6 mL, 192 mmol), and DARCO (2.0 g, 19.1 mmol) were combined in MeOH (200 mL). Ferric chloride (0.50 g, 3.1 mmol) was added, and the reaction was stirred at 70° C. for 3.5 hours. The mixture was stored in the freezer overnight, and then worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]1=S)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N([O-])=[O:23].[Na+].[OH-].[Na+]>Cl>[CH2:1]([N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]1=[O:23])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: S=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 3.02 g of (E)-1-cinnamyl-3-(3-pyridyl)imidazolidine-2-thione dissolved in 40 ml of 4N hydrochloric acid, 10 ml of an aqueous solution of 1.03 g of NaNO2 was added dropwise. After stirring at room temperature for 1 hour, the mixture was made alkaline by addition of a sodium hydroxide solution, and the precipitated crystals were collected by filtration. The crystals obtained were washed with water, dried and then purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=30:1), followed by recrystallization from ethanol, to give 1.74 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: NCC1(C)S(=O)(=O)C2SC=CC=2C1.[CH2:14]([C:17]1([C:27]([NH2:29])=O)[S:24](=[O:26])(=[O:25])[C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH2:18]1)[CH2:15][CH3:16]>>[NH2:29][CH2:27][C:17]1([CH2:14][CH2:15][CH3:16])[S:24](=[O:26])(=[O:25])[C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH2:18]1
Reactant: CCCC1(C(N)=O)Cc2ccsc2S1(=O)=O
Agent: CC1(CN)Cc2ccsc2S1(=O)=O
Product: CCCC1(CN)Cc2ccsc2S1(=O)=O
Yield: 77.6 %

Procedure:
The title compound was prepared substantially the same as 2-aminomethyl-2,3-dihydro-2-methylthieno[2,3-b]thiophene-1,1-dioxide. Thus, 2,3-dihydro-2-n-propylthieno[2,3-b]thiophene-2-carboxamide-1,1-dioxide (5.45 g, 21.0 mmol) reacted with borane-dimethyl sulfide complex (21 mL, 10M) to give, after work up, the title compound (4.0 g, 77%). 1H NMR (300 MHz,DMSO-d6) 0.95(t,3H), 1.35(m,2H), 1.80(m,1H), 2.00(m,1H), 2.80(d,1H), 2.95(d,1H), 3.10(d,1H), 3.23(d,1H), 7.05(d,1H), 8.05(d,1H).
Reaction SMILES: N=CCCC[C:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1)O.[NH:22]=[CH:23][CH2:24][CH2:25][CH2:26]CC(CC1C=CC=CC=1)(CC1C=CC=CC=1)O.C1(N(C2C=CC=CC=2)CCCCO)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)[Cl:82]>>[Cl:82][CH2:26][CH2:25][CH2:24][CH2:23][N:22]=[C:12]1[CH:11]=[C:8]([CH:6]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=[CH:14][CH2:13]1
Reactant: N=CCCCC(O)(Cc1ccccc1)Cc1ccccc1
Reactant: ClCCl
Reactant: N=CCCCCC(O)(Cc1ccccc1)Cc1ccccc1
Agent: OCCCCN(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCCCCN=C1C=C(C=Cc2ccccc2)C=CC1
Reaction time: 8 h

Procedure:
To prepare compounds 6c, 6d and 6f to a cooled 25 ml round-bottomed flask containing 5c (50 mg, 0.16 mmol), 5d or 5f and Ph3P (51 mg, 0.2 mmol) was added HCA (0.05 ml, 0.3 mmol) in 1 ml CH2Cl2. The reaction mixture was allowed to come to room temperature and stirred overnight. Flash silica gel column chromatography by eluting with hexane to remove the HCA followed by 5% ethyl acetate/hexanes afforded the following compounds:
Reaction SMILES: [C:1](=[O:16])([O:12][CH2:13][CH2:14][CH3:15])OC1C=CC([N+]([O-])=O)=CC=1.[NH2:17][C:18](=[NH:48])[C:19]1[CH:47]=[CH:46][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:45]=[CH:44][C:40]([C:41]([NH2:43])=[NH:42])=[CH:39][CH:38]=3)[CH2:29][CH2:28]2)=[CH:21][CH:20]=1.C(Cl)(Cl)Cl.[OH2:53]>CN(C)C=O>[NH2:48][C:18](=[N:17][C:1]([O:12][CH2:13][CH2:14][CH3:15])=[O:16])[C:19]1[CH:47]=[CH:46][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([NH2:43])=[N:42][C:1]([O:12][CH2:13][CH2:14][CH3:15])=[O:53])=[CH:44][CH:45]=3)[CH2:29][CH2:28]2)=[CH:21][CH:20]=1
Reactant: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O
Reactant: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOC(=O)N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NC(=O)OCCC)cc3)CC2)cc1
Reaction time: 4 h

Procedure:
Into a solution of 1.71 g of 4-nitrophenyl propyl carbonate in 15 mL of N,N-dimethylformamide, 1.50 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine was added at room temperature, and the solution was stirred at the same temperature for 4 hours. Chloroform and water were added to the reaction mixture. The organic layer was separated, washed with water, twice with a 5% potassium carbonate aqueous solution and with a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate, followed by solvent removal by evaporation under reduced pressure. The obtained residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=4:1). The obtained solid substance was dissolved in chloroform, washed with a 5% potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation under reduced pressure, 1.25 g of 4-{3-[4-(3-{4-[amino(propoxycarbonylimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-(propoxycarbonyl)benzamidine was obtained as a white solid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].C(OCC)C.[CH:14]([C@H:17]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:16])[CH3:15]>>[CH2:5]([C@:21]1([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:17]1[CH:14]([CH3:16])[CH3:15])[CH3:6]
Reactant: CC(C)[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (9.25 g), 3 mol/L ethylmagnesium bromide-diethyl ether solution (11.0 mL) and benzyl (2S)-2-isopropyl-3-oxopyrrolidine-1-carboxylate (3.92 g), the title compound was obtained as colorless oil (yield: 2.21 g, yield: 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1.CC(=CC)C.Cl([O-])=[O:19].[Na+]>CC(O)(C)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:19])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=Cc1cnc2ccc(Cl)nn12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (1.82 g, 10 mmol), in t-BuOH (90 mL) and 2-methyl-2-butene in THF (30 mL, 2.0 M) was added a solution of sodium chlorite (80%, 9.0 g, 100 mmol) and NaH2PO4 (1 g, 8 mmol) in water (45 mL). The mixture was stirred at rt for overnight, concentrated, diluted with water, acidified to PH=4, precipitated white solid, filtered to give 6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid as white solid (1.2 g, 67% yield)). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J=9.60 Hz, 1H), 8.22 (s, 1H), 7.50 (d, J=9.60 Hz, 1H); LRMS (ESI) m/e 198.1 [(M+H)+, calcd for C7H6ClN3O2 198.6].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[H-].[Na+].[CH3:26]I.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH3:26])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1
Reactant: CI
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
92 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine was dissolved in 1.5 ml of tetrahydrofuran, and 17 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 10 minutes. 26 μl of methyl iodide was added thereto, and the reaction solution was subjected to microwave irradiation at 100° C. for 5 minutes. 8 mg of 60% sodium hydride and 26 μl of methyl iodide were added to the reaction solution, and the reaction solution was stirred at 130° C. for 10 minutes, and furthermore 17 mg of 60% sodium hydride and 26 μl of methyl iodide were added, and the mixture was stirred at 130° C. for 10 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as pale yellow oil.
Reaction SMILES: [OH2:1].O.O.O.O.O.O.O.O.[S-2:10].[Na+:11].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=O.[OH-].[Na+]>O>[S:10]1[CH:18]=[CH:14][CH:15]=[C:16]1[C:17]([O-:1])=[O:13].[Na+:11]
Reactant: [S-2]
Reactant: O=C(Cl)c1ccco1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1cccs1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
60.0 g (0.250 mole, 1.39 eq) of sodium sulfide nonahydrate is dissolved in 508 ml of water. The solution is degassed by applying vacuum and releasing with nitrogen. The pH of the solution is adjusted to pH 10 by adding.85% phosphoric acid. 17 ml of ethyl acetate is added. 22.0 ml (density =1.324 29.1 g, 0.223 mole, 1.24 eq) of furoyl chloride is added dropwise while maintaining the pH of the solution at pH 9.0 to 9.5 by adding 25% sodium hydroxide solution. The furoyl chloride is rinsed in with 3 ml of ethyl acetate. Total addition time is approximately 30 minutes and the final temperature is 28°-30° C. When the reaction is complete, the pH is adjusted to pH 5.0 by adding 85% phosphoric acid and vacuum is applied to remove residual hydrogen sulfide After 10 minutes, the vacuum is released with nitrogen. When all of the hydrogen sulfide is removed, the solution is heated to 60° C. and the pH adjusted to 6.4 by adding a 25% sodium hydroxide solution.
Reaction SMILES: [CH3:1][Al](C)C.[C:5](=[C:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][C:9]1=[O:15])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:5]([CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][C:9]1=[O:15])([CH3:1])([CH3:7])[CH3:6]
Reactant: C[Al](C)C
Reactant: CC(C)=C1CCC(C)CC1=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
28.5 ml (33 mmol) of trimethyl aluminum as 10% solution in toluene is instilled in 4.56 g (30 mmol) of 2-isopropylidene-5-methyl-cyclohexan-1-one (pulegon) and 214.5 mg (1.5 mmol) of CuBr in 30 ml of ethyl acetate. The reaction solution is stirred 1 hour more at 25° C. 2 ml of water is carefully added for hydrolysis and stirred for 15 minutes more. The inorganic solid is suctioned off, washed again with ethyl acetate and the solution is concentrated by evaporation in a vacuum. Distillation of the crude product at 120° C./6 torr yields 3.4 g of 2-tert-butyl-5-methyl-cyclohexanone (70% of theory) as isomer mixture.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[S:5][N:4]=1.CS(C)=[O:14]>O>[S:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([CH2:2][OH:14])=[N:4]1
Reactant: CS(C)=O
Reactant: BrCc1nsc2ncccc12
Solvent: O
Product: OCc1nsc2ncccc12
Temperature: 80 °C
Yield: 31 %

Procedure:
A solution of the crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine (3.49 mmol) in dimethylsulfoxide (20 mL) was treated with water (4 mL) and the reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was diluted with water (100 mL), filtered through Celite, and was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, dried (magnesium sulfate), and concentrated to provide isothiazolo[5,4-b]pyridin-3-ylmethanol in 31% yield as yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)S([O-])(=O)=O.[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]([I+]C1C=CC=CC=1)=[C:22]2[OH:37]>>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:22]2[OH:37]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Reactant: CCNc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCN(c1ccccc1)c1c(O)c2cc(Br)ccc2[nH]c1=O

Procedure:
The title compound was prepared using N-ethylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[O:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1.[S-:15][C:16]#[N:17].[K+].II>>[C:2]([C:3]1[S:15][C:16](=[NH:17])[N:14]([CH:11]2[CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: N#C[S-]
Reactant: CC(C)(C)CC=O
Reactant: NC1CCOCC1
Agent: II
Agent: [K+]
Product: CC(C)(C)c1cn(C2CCOCC2)c(=N)s1

Procedure:
Commercially available 3,3-dimethylbutanal (Aldrich), tetrahydro-2H-pyran-4-amine (Matrix), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 315A to afford the title compound. MS (ESI+) m/z 241 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH3:22][NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH3:22])[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: CNC1CCCCCC1
Product: CN(C(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)C1CCCCCC1

Procedure:
This compound obtained as the hydrochloride salt, m.p. 180°-182° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and N-methylcycloheptylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:26])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C>[NH3:4].[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:13]([Cl:12])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CN1CCN(c2ccc(N)cc2Cl)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2Cl)CC1
Product: N
Yield: 39.5 %

Procedure:
Following the general procedure for amine displacement using 5,8-dibromoimidazo[1,2-a]pyrazine (0.20 g, 0.72 mmol), 3-chloro-4-(4-methyl-piperazin-1-yl)-phenylamine (0.263 g, 1.08 mmol) and DIPEA (0.19 mL, 1.08 mmol) in iPrOH (5 mL). Purification of the crude compound by silica gel column chromatography, eluting with 95:5 DCM:NH3 (7M in MeOH), affords the title compound (60 mg, 20%).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9](=[N:30][OH:31])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)[CH:11]=1>>[CH3:1][C:2]1[O:31][N:30]=[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:23])[CH2:18][CH2:17]3)[CH:11]=2)[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1

Procedure:
Acetic anhydride (3 mL) was added to 2,2-dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (215 mg) obtained in Example 26-1), and heated under reflux for 2 hours, then the excess acetic anhydride was evaporated away, the residue was diluted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 36 mg of the entitled compound as a colorless solid.