Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH3:23])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC)(=[O:30])[C:26]([O:28]C)=[O:27].[H-].[Na+].Cl>C(COC)OC.C1COCC1>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH2:23][C:25](=[O:30])[C:26]([OH:28])=[O:27])([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(O)C(=O)CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of N-Benzyl-4-Acetyl-4-(4-Chlorobenzyl)-piperidine (600 mg, 1.75 mmol) and dimethyl oxalate (310 mg, 2.63 mmol) in dimethoxyethane (20 mL) was treated with sodium hydride (105 mg of a 60% dispersion in mineral oil, 2.63 mmol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into 1 N aqueous HCl (200 mL) and extracted with ethyl ether (1×50 mL). The ether extract was discarded. The pH of the aqueous phase was adjusted to pH 8 and extracted with ethyl acetate (3×200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The crude ester thus obtained was dissolved in THF (5 mL) and 3 N HCl (20 mL) and heated to reflux for 1 hour. The reaction was then cooled to room temperature, and concentrated at reduced pressure. The residue was triturated with tetrahydrofuran and the solid collected by filtration and crystallized from isopropanol to give 200 mg of the title compound. mp. 189°-181° C.
Reaction SMILES: C[CH:2]([CH:5]([OH:8])[CH2:6][Cl:7])[CH2:3][OH:4].Cl[C:10]1[CH:11]=[C:12]([CH2:18][OH:19])[C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1>>[Cl:7][CH2:6][CH:5]([OH:8])[CH2:2][CH2:3][OH:4].[C:12]1([CH2:18][OH:19])[C:13]([CH2:16][OH:17])=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: OCc1ccc(Cl)cc1CO
Reactant: CC(CO)C(O)CCl
Product: OCCC(O)CCl
Product: OCc1ccccc1CO

Procedure:
Example 1 was repeated except for using 10.53 g (76 mmoles) of 2-methyl-4-chloro-1,3-butanediol and 6.00 g (35 mmoles) of 4-chloro-o-xylylene glycol, instead of 9.48 g (76 mmoles of 4-chloro-1,3-butanediol and 4.76 g (35 mmoles) of o-xylylene glycol, respectively, to obtain spiro[7-chloro-1,5-dihydro-2,4-benzodioxepin-4'-methylene-5'-methyl-3,2'-[1,3dioxane.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[C:17]([SH:28])=[N:16][CH:15]=1)=[O:13])=[O:7])(C)(C)C>C(O)=O>[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[C:17]([SH:28])=[N:16][CH:15]=1)=[O:13].[CH:6]([O-:7])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Solvent: O=CO
Product: NCCNC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Product: O=C[O-]
Reaction time: 3 h

Procedure:
A solution of N-(t-butyloxycarbonylaminoethyl)-1-(3,5-diflurobenzyl)-2-mercaptoimidazole-5-carboxamide acid (1.29 g, 3.13 mmole) prepared as above in 98% formic acid (40 ml) was stirred under an argon atmosphere for 3 hours and the solvent was removed under vacuum. The resulting oil was triturated with ether, and the product was filtered and dried to give N-(2-aminoethyl)-1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxamide, formate, m.p.: 195°-196° C. (0.630 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]2[NH:65][CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]=2[CH:67]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:65]2[CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]3[CH:67]=[C:53]([Cl:52])[CH:54]=[CH:55][C:56]2=3)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid from Example E9 (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (0.70 ml, 4.0 mmol), PyBrop (2.40 g, 5.1 mmol), and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc) to yield the title compound (775 mg, 91%).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:16][O:13][C:2]([CH3:1])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CI
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
In a round bottom flask was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (1.39 g, 7.51 mmol) dissolved in N,N-dimethylformamide (25 mL). To this solution was added sodium hydride (667 mg, 9.01 mmol, 60% dispersion in oil) and it was stirred for 15 min until gas evolution ceased. To this was then added methyl iodide (700 μL, 11.26 mmol) and it was stirred for 2 h at 25° C. The reaction was then quenched with water (250 mL). The reaction was transferred to a separatory funnel and extracted with ethyl acetate (250 mL). The organics were dried over sodium sulfate and then concentrated with silica gel (3 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 20% ethyl acetate/hexanes) to afford 1-(2-methoxy-2-methyl-propyl)-3-nitro-1H-pyrazole (1.33 g, 88%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:42][CH2:43]I>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:43][Cl:42])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(N-benzyloxycarbonyl-L-valyloxy)propanoic acid (5.2 g, 16.08 mmole) in 1,4-dioxane (50 ml) was added a 40% solution of tetrabutylammonium hydroxide (10.43 g, 16.08 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 40 ml dichloromethane and chloroiodomethane (28.4 g, 160 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.2 g=35%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:27][OH:28])[NH2:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([O:44]CC(O)=O)[C:38]1C=CC=CC=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:26]=[C:38]([CH2:37][OH:44])[O:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(N)=NO)cc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4noc(CO)n4)cc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-N′-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboximidamide (intermediate 55, 0.20 g, 0.38 mmol), 2-benzyloxyacetic acid (0.064 mg, 0.385 mmol), DIPEA (0.103 mg, 0.800 mmol), HOBt (0.108 g, 0.8 mmol), and DIC (0.073 g, 0.578 mmol) in DCM (3.85 mL) was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc, washed with dilute NaOH, 5% citric acid, dried (MgSO4) and concentrated to afford the desired product, which was used without further purification. LC/MS: m/e 667.5 (M+H)+.
Reaction SMILES: OC1C=C(N2C3C=NC(OC)=CC=3N=C2)SC=1C(OC)=O.[OH:22][C:23]1[CH:27]=[C:26]([N:28]2[C:36]3[CH:35]=[C:34]([O:37][CH3:38])[N:33]=[CH:32][C:31]=3[N:30]=[CH:29]2)[S:25][C:24]=1[C:39]([O:41][CH3:42])=[O:40].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58]>CN(C)C=O>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]2[N:30]=[CH:29][N:28]([C:26]3[S:25][C:24]([C:39]([O:41][CH3:42])=[O:40])=[C:23]([O:22][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:58])([F:59])[F:60])[CH:27]=3)[C:36]=2[CH:35]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.20 g of an isomeric mixture of methyl 3-hydroxy-5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate (example C6) in 15 ml anhydrous N,N-dimethylformamide were added 0.65 g of K2CO3 and 1.12 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature and poured into 400 ml of ice water. The resulting solid was filtered, washed with water and dried under vacuum to give the crude title compounds as an isomeric mixture. The isomeric mixture was used for the next steps (examples 16, 17 and 18) without further purification.
Reaction SMILES: CO[CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].B(F)(F)F.P(=O)([O-])[O-]>ClCl>[CH3:14][O:13][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[P:15]([O:19][CH2:20][CH3:21])(=[O:22])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(C(OC)OC)ccc1Cl
Agent: ClCl
Agent: FB(F)F
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(OCC)C(OC)c1ccc(Cl)c(OC)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of dimethyl acetal 3 (4.3 g, 20 mmol), sieve-dried CH2 Cl2 (20 ml) and triethyl phosphite (4.1 ml, 24 mmol) was stirred under argon at -78° C. Boron trifluoride ethereate (2.95 ml, 24 mmol) was added dropwise at -78° C., the solution was stirred 5 min and stored overnight at -20° C. The next day the reaction was warmed to room temperature and stirred 5 hours to complete phosphonate formation. With vigorous stirring, the reaction was quenched with solid NaHCO3 followed by 40 ml saturated NaHCO3 solution. After gas evolution ceased, 40 ml CH2Cl2 and 20 ml H2O were added, the biphasic mixture was partitioned and the CH2Cl2 phase was recovered, dried over Na2SO4 and evaporated. After pumping in vacuo, the oil was purified on a silica gel plug, eluting with CH2 Cl2 to yield phosphonate 4 as a light yellow oil (6.01 g., 99%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1.[S-2:24].[Na+].[Na+].O.Cl>CN(C=O)C.CO>[OH:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:24])[N:3]=[C:4]([O:22][CH3:23])[C:5]=2[C:20]#[N:21])=[CH:11][CH:12]=1
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 g (12.1 mmol) of 2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile are dissolved in 16 ml of anhydrous DMF, 1.42 g (18.2 mmol) of anhydrous sodium sulphide are added and the mixture is stirred at room temperature for 2 h. 36 ml of water are added, and with stirring the solution is slowly added dropwise to a mixture, warmed to 50° C., of 61 ml of 1M hydrochloric acid and 20 ml of methanol. The yellow suspension is stirred at RT for 1 h and filtered off with suction, and the precipitate is washed with water and dried at 45° C. under reduced pressure overnight.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH:9]([N:11]1[C:24]2[CH:23]=[C:22]([C:25](=S)[NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10].C(O)(=[O:35])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH:9]([N:11]1[C:24]2[CH:23]=[C:22]([C:25]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:35])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10]
Reactant: CC(=O)O
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
Mercuric acetate (2.91 g) dissolved in glacial acetic acid (60 cc) is added in the course of 20 minutes to a solution of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (4.29 g) in acetic acid (60 cc), and the mixture is stirred for 45 minutes at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc). The organic phase is washed successively with normal sodium hydroxide (2×100 cc) and distilled water (3×100 cc) and with saturated aqueous sodium chloride (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (4.6 g) is thereby obtained. This residue is purified by chromatography on a column (height: 25 cm; diameter: 3.0 cm) of silica gel (0.04-0.06 mm), eluting with pure ethyl acetate (3.6 liters) with a slight excess pressure of nitrogen (40 kPa) and collecting 150-cc fractions. Fractions 12 to 24 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2R)-2-h-ydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarboxamide, L series (0.89 g) in the form of an off-white solid, m.p. 140° C.
Reaction SMILES: [C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27]Cl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].C(=S)(SC)[NH2:33].[Na]>O>[C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][NH2:33])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(NC(=O)CCl)n1
Reactant: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(NC(=O)CN)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
To a solution of 0.10 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate in 5 ml of water is added under ice-cooling 0.030 g of sodium monomethyl dithiocarbamate, and the mixture is stirred for 3 hours at room temperature. The same procedure as Example 3B yields 0.016 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-aminoacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)O

Procedure:
This ester (3.2 g) was dissolved in ethanol (15 ml) and 2N-sodium hydroxide (15 ml) and left at room temperature for 1 hour. The acidic product was isolated by extraction with ether and purified by chromatography on silica gel to give 3-butyl-5-(6-carboxyhexyl)-1-octyl hydantoin as a colourless oil.
Reaction SMILES: Br.[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4]1.Cl[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:2][CH:3]1[CH2:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7][N:8]1[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1
Reactant: CC1CN(c2ccccn2)CCN1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 35.7 %

Procedure:
The product from Example 24A (0.50 g, 1.93 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was slowly treated with a solution of 2-chloromethyl-1H-benzimidazole (0.31 g, 1.83 mmol) in N,N-dimethylformamide (10 mL). After 5 minutes, the mixture was treated with cesium carbonate (0.60 mmol, 1.83 mmol) and the cooling bath was removed. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (2% methanol/dichloromethane) to afford 201 mg (36% yield) of the title compound. mp 207–209° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.18 (d, J=6.0 Hz, 3H), 2.38 (m, 1H), 2.52 (m, 1H), 2.78 (m, 2H), 3.02 (m, 1H), 3.67 (d, J=14.4 Hz, 1H), 3.97 (m, 2H), 4.08 (d, J=14.4 Hz, 1H), 6.62 (dd, J=5.1, 6.9 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.15; H, 6.92; N, 22.46.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(Cl)cc1

Procedure:
ninhydrin, 4-(4-chlorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8](C(O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)CCC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([NH2:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCO
Product: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (12.5 g, 38.3 mmol) in tent-butanol (250 mL) were added triethylamine (5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). The reaction mixture was stirred at 95° C. for 16 hours, then allowed to cool down to RT, and concentrated in vacuo. The resultant residue was dissolved in EtOAc, washed successively with water, aqueous saturated sodium bicarbonate solution followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (150 mL) and treated with TFA (50 mL). The reaction mixture was stirred at RT for 3 hours then concentrated in vacuo. The resulting residue was triturated with 20% EtOAc/cyclohexane and filtered to afford 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine as an off-white solid (7.94 g, 70%). LCMS: RT=3.13 min, [M+H]+=297/299
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:33][CH2:32]1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3cccc(Oc4ccccc4)c3)no2)CC1
Yield: 81.6 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.03 mmol) and 1-(2-methoxyphenyl)piperazine (13.2 mg, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (22 mg, 0.10 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.5 hr and followed the same processes as in Example 1 to obtain 11.5 mg (71.8%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](Cl)=[O:12].[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:12])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1CCC(CN)CC1
Reactant: O=C(Cl)c1c[nH]c2ccc(F)cc12
Product: CCCCN1CCC(CNC(=O)c2c[nH]c3ccc(F)cc23)CC1
Yield: 64 %

Procedure:
5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methylamine (Description 1a) as in the method of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 5-fluoroindole-3-carboxamide as an off-white solid (64%).