Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(F)ccc2n[nH]cc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To a solution of methyl 5-fluoro-2H-indazole-4-carboxylate (4.50 g, 23.2 mmol) in ethyl acetate (93 mL) was 25 added trimethyloxonium tetrafluoroborate (4.46 g, 30.1 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (4.10 g, yield 85%).
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O.C(=O)=O>O>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])=[O:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C=O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A 100 ml flask containing 10.0 g lactose and 50 ml water was warmed to 50° C. and treated with 80 mg lactase 30,000 enzyme as in Example 3. After 6 hours the solution was analyzed by HPLC and found to contain 10% lactose, 45% D glucose, and 45% D-galactose, based on the lactose added. The mixture was heated to 75° C. briefly to denature the protein, and was then filtered. A 2.5 cm interior diameter by 60 cm length glass column was packed with about 300 ml of BIO-RAD AG 50W-X8 resin in the calcium form, minus 400 mesh. BIO-RAD AG 50W-X8 is the trademark for a cationic ion exchange resin sold by Bio-Rad, Richmond CA. The column was heated to 70° C. The mobile phase was deionized water which had been filtered and degassed and which was pumped at a flow rate of 4.0 ml per minute. Typical pressure was 30 psig. The sample injection loop was 10 ml. The run time was approx. 55 minutes. The filtered reaction mixture described above was concentrated to 30% by weight solids, then injected in portions into the column. By using a refractive index detector to monitor the eluant, the mixture was separated into two groups of fractions. The combined first group of fractions contained 0.8 g of lactose and 4. 2 g D-glucose. The combined second group of fractions contained 0.3 g of D-glucose and 4.4 g of D-galactose. The second group of fractions was concentrated to 10% by weight solids for the isomerization step. The D-galactose solution, stirred at room temperature in a small flask, was treated with 2.0 g calcium hydroxide and 0.15 g calcium chloride, and the precipitate formed within 1.5 hours. The precipitate of calcium hydroxide - tagatose complex was neutralized with CO2 to give 2.2 g D - tagatose.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:13]1
Reactant: CC(=O)CCl
Reactant: Oc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(1-((1S,2R,4R)-Bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenol (compound no. 229) (27.0 mg, 0.1 mmol) was dissolved in DMF (0.5 mL) and treated with K2CO3 (100 mg, 0.72 mmol) followed by the 1-chloropropan-2-one (19 mg, 0.4 mmol) and Nal (100 mg, 0.66 mmol) and the reaction was allowed to stir at room temperature for 48 h. The crude reaction mixture was filtered, diluted with DMSO to 1 mL and purified by LC/MS (10-99 CH3CN—H2O gradient with 0.03% TFA, 9 minute) to provide 1-(2-(1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)phenoxy)propan-2-one (compound no. 53) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 327.0 [M+H]+, retention time 2.32 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]>O1CCCC1>[ClH:24].[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: Clc1ccccc1C=Cc1ccccc1OCCCCBr
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCCCOc1ccccc1C=Cc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a mixture of 50 ml of tetrahydrofuran and 50 ml of aqueous 50% dimethylamine solution 5 g of 2-(4-bromobutoxy)-2'-chlorostilbene was dissolved and the resulting solution was stirred for 20 hours at ambient temperature. After the reaction was complete, the solvent was distilled off at reduced pressure. An aqueous 2 N NaOH solution was added to the residue and the mixture was extracted with ether. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. To the extract an ethanolic 20% hydrogen chloride was added to give 2-(4-dimethylaminobutoxy)-2'-chlorostilbene hydrochloride as a precipitate, which was then collected by filtration and recrystallized from ethanol-ether. Yield 4.7 g (94%). The data of melting point and elemental analysis are reported in the line of No. 1 in Table 2. Various compounds were also prepared in a similar manner. The data for these compounds are shown in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5](OCC2CO2)[CH:4]=1.C(N)(C)(C)C>C(O)C>[NH:14]1[C:15]2[C:11](=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(OCC2CO2)c1
Solvent: CCO
Solvent: CC(C)(C)N
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)cc1

Procedure:
Using the procedure of Step E of Example 52, 6 g of the product of Step B, 100 ml of ethanol, 9.2 ml of tert.-butylamine were refluxed for 3 hours to obtain 6.1 g of 2-[2-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy]-N-(1H-indol-4-yl)-4-methoxy-benzamide. The product was dissolved in 300 ml of refluxing of isopropanol and 1.8 g of benzoic acid were added thereto. The mixture was partially concentrated, iced and filtered and the product was dried under reduced pressure to obtain 5.1 g of the benzoate salt melting at 195° C. after crystallization for ethanol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[CH3:27][NH2:28].O>CN(C)C=O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH:15]1[CH2:14][C:13](=[O:26])[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:28]1[CH3:27]
Reactant: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(c2ccc3ccccc3c2)CC(=O)CC1c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
1,5-Bis(2-naphthyl)-1,4-pentadien-3-one (25, 0.82 g, 2.5 mmol) was dissolved in dimethyl formamide (15 ml). Methylamine (51, 1.30 ml, 15.1 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (100 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized twice from ethanol to give 0.20 g (22%) of a white solid: mp 209-212° C.; 1H NMR δ 1.89 (s, 3H), 2.59 (d, 2H, J=13.9 Hz), 2.97 (t, 2H, J=11.3 Hz), 3.66 (d, 2H, J=11.7 Hz), 7.49 (m, 4H), 7.81 (m, 10H); 13C NMR: δ 41.1, 50.7, 70.3, 124.6, 125.9, 126.0, 126.2, 127.6, 127.7, 128.9, 133.0, 133.4, 140.4, 206.6; Exact mass calcd for C26H23NO: 365.1780, observed (M+H) 366.1852.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)=O)[CH2:7]1)=[O:5])C.[OH-].[Li+:26].C1COCC1>O>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@:6]([CH3:24])([C:4]([O-:5])=[O:3])[CH2:7]1.[Li+:26]
Reactant: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(C(=O)[O-])CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 74.2 %

Procedure:
(S)-1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (512 mg, 1.60 mmol), 1 M lithium hydroxide (4.81 ml, 4.81 mmol) and THF:H2O solution (9:1) (5 ml) were heated under microwaves at 100° C. for 26 h. The mixture was filtered and evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc and the aqueous phase was evaporated to dryness to give 353 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][NH:10][CH3:11].[CH2:12]=O>O>[CH3:9][N:10]([CH2:12][C:3]1[C:2]([OH:1])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1)[CH3:11]
Reactant: C=O
Reactant: CNC
Reactant: Cc1ccncc1O
Solvent: O
Product: Cc1ccnc(CN(C)C)c1O

Procedure:
A solution consisting of 3-hydroxy-4-methylpyridine (32.7 g.), 30% aqueous dimethylamine (46.5 ml.) and formalin (25 ml.) in water (50 ml.) was heated on a steam bath for a period of two hours. The cooled reaction solution was then extracted with ten-100 ml. portions of diethyl ether and the combined ether and extracts were subsequently dried over anhydrous magnesium sulfate and filtered. After removal of the volatile liquids by means of evaporation under reduced pressure, there was finally obtained an oil as residue which was subsequently distilled in vacuo to give pure 2-dimethylaminomethyl-3-hydroxy-4-methylpyridine (yield, 34.5 g.), b.p. 71°-74° C./0.6 mm. Hg. The corresponding dihydrochloride salt melted at 214°-217° C. (decomp.) after recrystallization from ethanol/diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22][CH3:23])[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:24][O:12][C:11](=[O:13])[C:10]1[C:14]([O:22][CH3:23])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(OC)cc(C(F)(F)F)cc1OCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 380 mg (1.165 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzoic acid in 3.8 ml N,N-dimethylformamide under nitrogen at room temperature, was added 177.1 mg (1.281 mmol) potassium carbonate and 87.2 ul (1.398 mmol) methyliodide. The mixture was stirred under nitrogen for 3 days. The mixture was poured into water. The aqueous layer was extracted once with ethyl acetate. The organic layer was washed once with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude light yellow oil (410 mg) was purified with flash column chromatography on silica (10 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>10% in 15 minutes) to provide 352 mg (y: 88.8%) of the title compound as a colorless oil, which crystallized on standing. MS (m/e): 341.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation analogous to US 2005/59668) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]1(O)C2C(=CC=CC=2)C=CC=1.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23].BrNC(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:23][CH3:1]
Reactant: Oc1c(Br)ccc2ccccc12
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(C)NBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(Br)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-naphthol was converted into 2-bromo-1-naphthol by reaction with a slurry of N-bromo-t-butylamine at -78° C. according to the procedure described in Pearson, Wysong, Breder, J. Org. Chem. 32, 2358 (1967). To a solution of 1 mole (crude) of the bromonaphthol in 750 mL of acetone was added 175 g of potassium carbonate. Over a 2-hous period, 95 mL of dimethylsulate was added dropwise to the mechanically stirred reaction mixture. The resulting slurry was stirred at 25° C. overnight. The solids were filtered and the solution was stripped to yield a dark brown oil. Initial purification was accomplished by vacuum distillation (80°-120° C., 0.2 Torr) followed by further purification by HPLC with hexane to yield 145 g of 2-bromo-1-methoxynaphthalene as a pale yellow oil. NMR confirmed the structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:5])C>CO.C1COCC1.O>[Cl:22][C:19]1[S:18][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:11][N:7]3[CH:8]=[CH:9][CH:10]=[C:6]3[C:4]([OH:5])=[O:3])[CH:16]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Yield: 119.6 %

Procedure:
To a solution of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (135 mg) in MeOH/THF/H2O (3:1:1, 5 mL) was added LiOH monohydrate (100 mg). The mixture was refluxed for 2 h after which it was cooled to RT and concentrated. The mixture was acidified by the addition of 1 N aqueous KHSO4 solution and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (148 mg) which was directly used in the next step. MS (ESI−): m/e=307 [M−H]−, chloro pattern.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]1([C@H:14]([N:21]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([F:12])([F:11])[F:1])[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](N=C(c1ccccc1)C(F)(F)F)c1ccccc1
Yield: 100.1 %

Procedure:
A solution of 2,2,2-trifluoroacetophenone (7.0 g, 40 mmol), R-(+)-α-methylbenzylamine (7.75 mL, 60 mmol), and p-toluenesulfonic acid monohydrate (0.77g, 4.0 mmol) in toluene (40 mL) was refluxed for 18 hours with a Dean-Stark trap. After cooling, the reaction mixture was diluted with toluene (50 mL), washed with 5% NaOH (1×50 mL), saturated NH4Cl (4×30 mL) and brine, dried over MgSO4, concentrated and dried at room temperature in vacuum to give the title compound as pale yellow liquid (11.1 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]1[O:15][C:8]2([CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[O:7][CH2:6]1.[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18]>C(O)C.C(O)(C)C.CO.[Pd]>[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18].[CH2:5]1[O:15][C:8]2([CH2:13][CH2:12][CH:11]([NH:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH2:9]2)[O:7][CH2:6]1
Reactant: CCCN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: CCCNC1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
N-propylamine (88.5 g, 123 mL, 1.5 mol) is added to a solution of 1,4-cyclohexanedione monoethylene ketal (156 g, 1 mol) in ethanol (780 mL). 5% Pd/C (50% water) is added to the mixture. The mixture is hydrogenated at 3 bar for several hours. Once the reaction has ended, the solvent is eliminated and the residue is dissolved in isopropanol (1.560 mL). A solution of oxalic acid (132 g, 1.5 mol) in MeOH (200 mL) is added dropwise to this solution. The suspension is stirred for 30 minutes and filtered on a plate, obtaining 274 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:21]([N:23]1[C@H:28]([CH3:29])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@@H:24]1[CH3:37])=[O:22]>>[CH3:37][C@H:24]1[CH2:25][NH:26][CH2:27][C@@H:28]([CH3:29])[N:23]1[C:21]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:22]
Reactant: BrCCc1ccccc1
Reactant: OCc1cc(O)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCCc2ccccc2)ccc1F

Procedure:
2-Fluoro-5-(2-phenyl)ethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 2-phenylethyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (2.2%); HPLC (XTERRA, 50/80, 220 nm) 87.7% (5.58 min); NMR δH (400 MHz, DMSO-d6) 1.168(6H, d, J 7.0 Hz), 2.685(4H, m), 3.020(2H, t, J 7.0 Hz), 3.915(2H, m), 4.175(2H, t, J 7.0 Hz), 5.079(2H, s), 6.940(2H, m), 7.132(1H, t, J 9.0 Hz), 7.224(1H, m) and 7.308(4H, m).
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][C:14](=N)N)[N:11]=1)[C:4]([NH2:6])=[NH:5].[OH-:17].[Na+].[S:19]([NH:23][C:24](=N)[CH:25]=C)(=[O:22])(=[O:21])[NH2:20]>CO>[S:19]([NH:23][C:24](=[O:17])[CH2:25][CH2:14][S:13][CH2:12][C:10]1[N:11]=[C:7]([NH:3][C:4]([NH2:6])=[NH:5])[S:8][CH:9]=1)(=[O:22])(=[O:21])[NH2:20]
Reactant: N=C(N)Nc1nc(CSC(=N)N)cs1
Reactant: C=CC(=N)NS(N)(=O)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCC(=O)NS(N)(=O)=O)cs1
Reaction time: 0.5 h

Procedure:
To a solution of S-(2-guanidino-4-thiazolylmethyl)isothiourea dihydrochloride (307 mg, 1.0 mmol) in methanol (5 ml) under a nitrogen atomosphere there was added 1.0 N sodium hydroxide (3 ml, 3.0 mmol). After stirring for 1/2 hour, a solution of N-sulfamyl acrylamidine (169 mg, 1.0 mol) in methanol (3 ml) was added. There was an instantaneous reaction to give product as indicated by TLC. After stirring for several hours, solvents were evaporated and the residue chromatographed on silica gel eluting with 10-15% methanol/chloroform to obtain pure product. When these fractions were combined and evaporated and the residue dissolved in a minimum amount of methanol and diluted with chloroform, the product slowly crystallized, 120 mg, mp 160°. A mixed melting point with authentic product was not depressed.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:10]([O:5][C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][N:1]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1)=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCCNC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 44.9 %

Procedure:
To a solution added of nipecotic acid (8.0 g, 61.9 mmol) in N,N-dimethylformamide (80 mL) is benzyl bromide (31.8 g, 186 mmol) and potassium carbonate (42.8 g, 310 mmol). The mixture is heated at 70° C. for 18 hours and diluted with ethyl acetate and water. The organic extract is washed with 1.0 M hydrochloric acid, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (8.6 g). 1H NMR (200 MHz, DMSO-d6): δ 7.27-7.42 (m, 10H), 5.07 (s, 2H), 3.45 (s, 2H), 2.88-2.49 (m, 3H), 2.32-1.32 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][NH:9][CH2:10]2)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][N:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[S:27][C:26]4[N:28]=[CH:29][CH:30]=[N:31][C:25]=4[NH:24][C:23]=3[CH:32]=1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C2CNCC21
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C2CN(Cc3ccc4c(c3)Nc3nccnc3S4)CC21
Temperature: 80 °C
Yield: 28 %

Procedure:
To a solution of 1.523 g of ethyl(3-azabicyclo[3.1.0]hex-6-yl)carboxylate in N,N-dimethylformamide (30 ml) were added 2.30 g of sodium hydrogencarbonate and 1.39 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 80° C. for 2 hours. After adding water and ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.574 g of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11].CC(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: O
Solvent: CCC(C)O
Product: NNc1ccc(Br)cn1
Reaction time: 20 h
Yield: 87 %

Procedure:
A 12 L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55% wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3×200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87%).