Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][C:9]([C@@H:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O1CCCC1.O>[CH2:27]([O:26][C:24]([C@@H:12]1[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19])[CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:25])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
To a solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclopentane-1,2-dicarboxylic acid 1-ethyl ester 2-(tert-Butyl-dimethyl-silanyl) Ester (epimeric mixture, 12.09 g) in ethanol (340 mL) and tetrahydrofuran (114 mL) was slowly added a solution of potassium carbonate (16.68 g) in water (114 mL). After 45 min at room temperature, the solvents were removed in vacuo. Brine was added to the residue and the mixture was cooled to 0° C. then the pH was adjusted to 4-5 using a 10% aqueous solution of potassium hydrogenosulfate. The resulting mixture was extracted with diethylether. The combined organic layers were washed with brine then dried over sodium sulfate and concentrated in vacuo to afford the title compound (8.03 g, 90%) as light yellow oil, used in the next step without further purification. MS (EI): 315.2 (M−H)−.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(F)c1
Yield: 56 %

Procedure:
Using ethanamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (56% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.24, 5.56 Hz, 2 H) 7.55 (dt, J=10.48, 8.40 Hz, 1 H) 7.73 (m, J=7.33, 4.74, 2.08, 1.14, 1.14 Hz, 1 H) 7.88 (ddd, J=11.75, 7.83, 2.15 Hz, 1 H) 8.58 (t, J=4.93 Hz, 1 H). ESI-MS: m/z 186.1 (M+H)+. mp=94.1-96.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.1 g, 3.94 mmol) and Pd/C (10% wt) (0.419 g, 0.394 mmol). EtOH (16 mL) was added, and the reaction mixture was purged with nitrogen 3 times. A H2-filled balloon was attached to the top of the flask, and the mixture stirred at RT for 2 hours. The reaction mixture was diluted with EtOH and filtered through Celite® brand filter aid. The pad was washed with DCM (50 mL), EtOH (50 mL), and MeOH (50 mL). The filtrate was concentrated to dryness to afford cis-methyl 4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate as a purple oil. (0.9 g, 92.0% yield). MS m/z=250.2 [M+H]. Calc'd for C13H19N3O2: 249.2.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:4]1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[CH2:4]3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N[C@@H]1CCN(C(=O)c2cccc(O)c2)C1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(C(=O)c3cccc(O)c3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxybenzoyl)pyrrolidine hydrochloride, as described above in Step B, (350 mg, 1.44 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde as described in Example 1, Step G (363 mg, 1.58 mmol), were stirred in MeOH (8 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (109 mg, 1.73 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CHCl3—3% MeOH—0.4% NH4OH to CHCl3—6% MeOH—0.6% NH4OH to yield the titled product as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[F:21].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[F:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Cl)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc([C@@H]2CNCCO2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 2-(4-chloro-3-fluorophenyl)morpholine-4-carboxylate (990 mg) was dissolved in 2 mL of dichloromethane and TFA (2 mL) was added. The solution was stirred at room temperature for 2 h. Solvents were evaporated. The residue was extracted with dichloromethane and 1N NaOH solution. The organic layer was dried and concentrated. The residue was dried in vacuum to afford (R)-2-(4-chloro-3-fluorophenyl)morpholine an oil (669 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.11 (br. s., 1H) 2.72 (dd, J=12.38, 10.36 Hz, 1H) 2.86-3.04 (m, 2H) 3.07 (dd, J=12.38, 2.53 Hz, 1H) 3.79 (td, J=11.37, 3.03 Hz, 1H) 4.05 (dd, J=11.49, 2.40 Hz, 1H) 4.48 (dd, J=10.36, 2.53 Hz, 1H) 7.02-7.13 (m, 1H) 7.15-7.23 (m, 1H) 7.33-7.42 (m, 1H).
Reaction SMILES: [CH3:1]C1C=NC=C(C=1)C(O)=O.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21](C(F)(F)F)=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH3:1])[C:23]=1[I:24])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Reactant: Cc1cncc(C(=O)O)c1
Product: Cc1cncc(NC(=O)OC(C)(C)C)c1I

Procedure:
The title product was prepared from 5-methylnicotinic acid in the same manner as in the preparation of (4-iodo-6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[Br:26]Br>C(O)(=O)C.[Fe]>[ClH:22].[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:24])[C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])=[C:12]([Br:26])[CH:13]=1)[NH2:6]
Reactant: BrBr
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Reference Example 56 was prepared as follows: To a solution of 4-[(2,6-Dichlorobenzoyl)amino]-L-phenylalanine methyl ester hydrochloride salt, 37-B-1, (205.7 mg) in acetic acid(5 mL) was added an excess of bromine (5.55 g) in acetic acid (5 mL) and iron powder (416.2 mg). The reaction was stirred at ambient temperature for 3 hours. The reaction concentrated in vacuo and the remaining acetic acid removed as an azeotrope with toluene. The crude material was diluted with water, made basic with saturated sodium bicarbonate and extracted with AcOEt. The extract was purified by flash chromatography on silica gel eluting with methanol-methylene chloride. The purified material was dissolved in methanol saturated with hydrogen chloride and concentrated in vacuo and then crystallized from methanol with AcOEt to obtain 3-Bromo-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester hydrochloride salt (540.4 mg). Physical properties as follows: m.p. 200-205; 1H NMR (CD3OD) δ 7.76 (1H), 7.64 (1H), 7.46 (3H), 7.34 (1H), 4.38 (1H), 3.85 (3H), 3.30 (1H), 3.15 (1H); HRMS (FAB) Calcd for C17H15BRCL2N2O3+H1 444.9722, found 444.9724.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][CH3:30]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][CH3:30])[CH2:17][CH2:16]1
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 353 (M+, 1), 325 (15), 324 (bp), 191 (37), 133 (14).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(N)c(C#N)cc1OC
Temperature: 90 °C
Yield: 97.2 %

Procedure:
A suspension of 2-nitro-4,5-dimethoxybenzonitrile (6.0 g, 28.8 mmol) in water (200 mL) was heated to 90° C. To this hot mixture was added sodium dithionite in a small portion until it was dissolved completely. The resulting solution was filtered and then cooled to room temperature to get crystal. The solid was collected by filtration to afford 4.99 g (97%) of 2-amino-4,5-dimethoxybenzonitrile. An analytical sample was recrystallized from acetonitrile. 1H NMR (100 MHz, DMSO-d6): δ3.64 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.32 (br s, 2H, NH2), 6.41 (s, 1H, Ar--H), 6.86 (s, 1H, Ar--H). 13C NMR (25 MHz, DMSO-d6): d 55.55, 56.87, 83.67, 92.08, 113.96, 140.33, 148.12, 154.33. MS: m/z 178 (M+), 163 (M+ -15), 147 (M+ -31), 135 (M+ -43), 120 (M+ -58).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][N:10]=[C:11]([OH:12])[C:6]=2[CH:5]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[OH:12][C:11]1[C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:16])[CH3:15])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: NCCc1cc2c(O)ncnc2s1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NCCc1cc2c(O)ncnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen was added a solution of 6-(2-aminoethyl)thieno[2,3-d]pyrimidin-4-ol (570 mg, 2.92 mmol, 1.00 equiv) in 10 mL of dichloromethane. TEA (1.2 g, 11.86 mmol, 4.06 equiv) and acetyl chloride (460 mg, 5.86 mmol) were added at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 400 mg (crude) of the desired N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)acetamide as a white solid. MS (ES): m/z 238 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=1)(=[O:3])[NH2:2]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:21][CH:22]=1)(=[O:3])[NH2:2]
Reactant: COCCOc1ccc(OCC(O)CN(CCCCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1
Solvent: CO
Product: COCCOc1ccc(OCC(O)CNCCCCOc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 25 g of crude 1-[N-[4-(3-carbamoyl-4-hydroxyphenoxy)butyl]benzylamino]-3-[4-(2-methoxyethoxy)-phenoxy]propan-2-ol in 250 ml of methanol is hydrogenated and worked up analogously to Example 4. The resulting crystalline crude product is recrystallised from isopropanol and yields 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol having a melting point of 122°-124°.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].CN(C)C1C=CC(C=N[N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=CC=1>C(#N)C>[Br-:1].[C:24]1([CH2:23][CH2:22][C:18]2[NH:17][CH:21]=[CH:20][N+:19]=2[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CN(C)c1ccc(C=Nn2ccnc2CCc2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)C(=O)C[n+]1cc[nH]c1CCc1ccccc1
Product: [Br-]
Reaction time: 24 h

Procedure:
8.0 g of 1-bromo-3,3-dimethyl-butan-2-one are added to 0.64 g of 1-[[p-(dimethylamino)-benzylidene]amino]-2-(phenylethyl)imidazole in 60 ml of acetonitrile. After stirring for 24 hours, the product is removed by filtration. There is obtained 3-[p-(dimethylamino)benzylidene]amino]-2-(phenylethyl)-1-(pivaloylmethyl)imidazolium bromide of melting point 231°.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH2:20].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH2:12]([N:11]1[C:7]([NH:6][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:8]([C:19](=[O:21])[NH:20][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[N:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)CC(=O)Cl
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Agent: O=S(=O)(O)O
Product: CC(C)CC(=O)NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)CC(C)C
Temperature: 0 °C

Procedure:
Concentrated sulphuric acid (7.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-1-benzyl-4-carbamoyl-1,2,3-triazole (10.85 g.; prepared as described by J. R. E. Hoover and A. R. Day, J.Amer.Chem.Soc., 1956, 78, 5832) in isovaleryl chloride (50 ml.), and the mixture was then stirred at room temperature overnight. The resulting solution was poured into ice-water, and the precipitated solid filtered off, stirred well with water, again filtered off, and dried, to give 1-benzyl-5-isovaleramido-4-isovalerylcarbamoyl-1,2,3-triazole (16.4 g.), m.p. 125°-128° C. An aliquot was recrystallised from di-isopropyl ether to give pure 1benzyl-5-isovaleramido-4-isovalerylcarbamoyl-1,2,3-triazole, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14]
Reactant: CN(C)CCCN
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Solvent: C1CCOC1
Product: CN(C)CCCNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: -40 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution containing 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinyl chloride in about 170 milliliters of THF was prepared in accordance with Example 1, chilled to -40° C. and treated, by slow dropwise addition, with a solution containing 0.026 moles of 3-dimethylaminopropylamine, in 25 milliliters of THF. The resulting slurry was stirred overnight at ambient temperature, filtered, the filtrate was concentrated by rotary evaporation, and vacuum distilled at 119° C./0.45 millimeter of mercury to produce a 40% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(3-dimethylaminopropyl)phosphinic amide. NMR characterization confirmed the product was 99% pure. Elemental analysis confirmed the structure contained the following:
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C=O.O>[N:23]1([CH2:22][CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1OCCCN1CCOCC1

Procedure:
Salicylaldehyde (17g) is treated first with 6.7g of 50% sodium hydride in 110 ml of dimethylformamide and then with 92 ml of a 2N toluene solution of N-(3-chloropropyl)-morpholine. The mixture is heated at 105°-110° C for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 32.3g of product as an oil, boiling point 155°-160° C at 0.1-0.2 mm of Hg.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](=[S:19])[N:16]([CH3:20])[C:15]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([C:15]2[N:16]([CH3:20])[C:17]([S:19][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:18][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCBr
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)[nH]c(=S)n2C)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC(C)=O)c2)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (3.1 mmol/0.34 g) is added to undissolved N-{4-[5-(4-fluorophenyl)-3-methyl-2-thioxo-2H-imidazol-4-yl]pyridin-2-yl}acetamide (2.23 mmol/0.8 g), and the mixture is then suspended in 100 ml of absolute acetone. Ethyl 3-bromopropionate (2.3 mmol/0.422 g) are then added, and the mixture is stirred at room temperature for 24 h. The mixture is then heated under reflux for 3 h, the precipitate is filtered off and the filtrate is concentrated under reduced pressure using a rotary evaporator. The oily residue is separated on a column (mobile phase: CH2Cl2/EtOH, 9.5:0.5).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCN)s1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccc(C)s1
Yield: 78 %

Procedure:
In close analogy to the procedure described above, 2-(5-Methyl-thiophen-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[CH3:26])[N+:13]([O-])=[C:14]3[CH3:17])=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:30]>ClCCl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=[CH:9]3)=[C:14]([CH2:17][OH:30])[N:13]=2)[CH:24]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C)[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a slurry of 7-(cyclopropanecarboxamido)-3-(5-fluoro-2-methylphenyl)-1-methyl-2,6-naphthyridine 2-oxide (100 mg, 0.3 mmol) in dichloromethane (3 mL) was added trifluoroacetic anhydride (0.08 mL, 0.57 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (50 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.31 (s, 1H), 8.89 (s, 1H), 8.06 (s, 1H), 7.43-7.33 (m, 2H), 7.19 (td, J=8.4, 2.6 Hz, 1H), 5.43 (t, J=5.4 Hz, 1H), 5.00 (d, J=5.4 Hz, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=4.553 min, M+H+=352.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:19]>C(COC)OC>[N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[NH:10][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][Cl:24])([O-:3])=[O:2]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Product: O=C(Nc1ccc(O)cc1[N+](=O)[O-])OCCCCl
Reaction time: 1 h

Procedure:
77 g (0.5 mole) of 3-nitro-4-aminophenol are dissolved in 200 ml of dimethoxy ethane, 27 g of calcium carbonate are added, and 80 g (0.51 mole) of γ-chloropropyl chloroformate are added dropwise at 70° C. After 1 hour, the reaction mixture is filtered hot and the filtrate is stirred into 700 ml of ice-water, after which 128 g (93%) of the desired compound precipitate. The melting point is 103°-105° C., and after recrystallisation from toluene is 106° C.
Reaction SMILES: CO[C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8](S(CC3C(C)=C(OC)C(C)=CN=3)=O)=[N:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O.O>ClCCl>[NH:7]1[C:6]2[CH:23]=[CH:24][CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
The sulfoxide solution was treated with triethylamine (25.4 mL). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (13.5 g) in dichloromethane (30 mL) was added while keeping the temperature below 10° C. After stirring for 2-3 hours, water (90 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (60 mL). The combined organic phases were washed with brine (60 mL) and saturated sodium bicarbonate (30 mL) and vacuum distilled to 90 mL. Ethyl acetate (180 mL) was added to the solution and vacuumed distilled to 90 mL. The solution was stirred while 150 mL of heptanes was added at 20-25° C. The suspension was cooled to 0-5° C. and maintained at this temperature for 2-3 hours. The suspension was filtered and the damp cake was pulped in ethyl acetate (30 mL) and heptanes (120 mL) for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) (2×30 mL) and dried under vacuum at room temperature to afford 5/6-methoxy-1-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Weight: 25.91 g. Yield: 59%. Ratio of 5- and 6-methoxy products: 3:2. The analytical data was consistent with the assigned structure.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[OH2:13].[CH:14]1[CH:19]=CC=CC=1>>[O:1]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:12]=[CH:14][CH:19]1[OH:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Reactant: O
Product: OC1C=Cc2ccccc2O1

Procedure:
The above oil is very oxidatively unstable and was immediately dissolved in about 200 ml of benzene containing p-toluenesulfonic acid monohydrate (500 mg, 2.63 mmole). The benzene solution was heated for about 2 hours under reflux with water removal facilitated by a Dean-Stark apparatus. The cooled benzene mixture was washed with aqueous NaHCO3, dried (brine, MgSO4) and stripped in vacuo to give crude [12a] isolated as a dark gum (4.86 g).