Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)(Cl)=O.[CH2:32](OCC)C>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:32])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOCC
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C(=O)O)nc3)[nH]n2)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Temperature: 50 °C
Yield: 47 %

Procedure:
To a stirred suspension of 5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic acid (55 mg, 0.15 mmol, 1 eq) in methanol (0.5 mL) was added thionyl chloride (23 uL, 0.32 mmol, 2.1 eq) dropwise. The resulting solution was heated at 50° C. for 3 h. The mixture was concentrated in vacuo to yield an orange solid. This was dissolved in DCM and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers were dried over magnesium sulphate, filtered and concentrated to give the crude product as a yellow solid. Trituration with diethyl ether gave the title compound as a white solid 27 mg (47%); 1H NMR (400.13 MHz, DMSO) δ 2.92 (4H, s), 3.74 (3H, s), 3.92 (3H, s), 6.49 (1H, s), 6.25 (1H, m), 6.82 (2H, m), 7.19 (1H, t), 8.14 (1H, d), 8.46 (1H, m), 9.20 (1H, d), 11.11 (1H, s), 12.25 (1H, s) MS m/z 381 (MH+)
Reaction SMILES: CC1C2C(=O)OC(=O)[NH:11]C=2C=CC=1.OC[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CS(O)(=O)=O.CCOCC>[C:17]([NH2:11])(=[O:26])[C:18]1[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:20]([NH2:16])=[O:21]
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 168.5 %

Procedure:
To a solution of 5-methyl-4H-3,1-benzoxazin-2,4-dione (Preparation VIIA) (19.7 g, 111 mmol) in methanesulfonic acid (150 mL) was added N-(hydroxymethyl)phthalimide (20.3 g, 111 mmol). The reaction mixture was heated to 50° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with 2000 mL of Et2O. After stirring for an additional 1 hour, the precipitate was filtered, washed with Et2O and dried affording 30.7 g of crude phthalamide. 1H NMR showed a 3:2 mixture of the 6- and 8-substituted regioisomers respectively. The crude material was used directly in the next reaction where the two regeoisomers were separated.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2=O)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16]3[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[NH:7][C:17]=32)=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)-c1[nH]c3ccccc3c1C2
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (1.21 mL, 1.33 g, 12.3 mmol) and 6-methoxy-1-indanone (2.01 g, 12.4 mmol) in ethanol (20 mL) was added glacial acetic acid (4 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Upon cooling, pale yellow crystals precipitated out of solution. Crystals were collected via vacuum filtration and dissolved in isopropanol (41 mL) Sulfuric acid (36 N, 1.39 mL) was added via syringe and the resulting solution was stirred at reflux (90° C.) for 18 hours—some precipitate formed over the course of the reaction. Upon cooling to room temperature, the solution was basified to pH 10 with aqueous sodium hydroxide (2% by mass) resulting in the formation of additional precipitate. The solid was collected by vacuum filtration to yield a brown solid which was subsequently dissolved in ethyl acetate (10 mL), diluted with H2O (10 mL), and extracted 1×15 mL dichloromethane to remove excess water. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to yield a brown solid in 61% crude yield (1.76 g, 7.50 mmol). Crude product was brought on to the next step without further purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 hexanes-ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.28 (s, 1H), 7.64-7.65 (d, 1H, J=7.2 Hz), 7.42-7.44 (m, 2H), 7.16-7.21 (qd, 2H, J=7.2, 1.2 Hz), 7.03-7.04 (d, 1H, J=2.4 Hz), 6.77-6.78 (dd, 1H, J=7.8, 2.4 Hz), 3.89 (s, 3H), 3.68 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 159.0, 143.1, 140.6, 139.8, 136.1, 125.7, 124.8, 123.2, 121.8, 120.2, 119.0, 112.0, 109.9, 103.8, 55.6, 29.5. FTIR: cm−1 3390, 2934, 1609, 1577, 1528, 1467, 1274, 1251, 1037, 837, 745: Calcd. for C16H14ON+ [M+H]+: 236.1070, found 263.1071.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH3:20])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Oc1ccccc1O
Reactant: CCOP(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOP1(=O)Oc2ccccc2O1
Yield: 95.1 %

Procedure:
Pyrocatechol (1.249 g, 11.35 mM) was dissolved in 42 ml of ether and, using 2.297 g (22.70 mM) of triethylamine and 1.849 g (11.35 mM) of ethyl dichlorophosphate, the reaction was carried out at -40° C. to -35° C. and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 2.159 g (95.0% yield) of ethyl o-phenylene phosphate as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]N)=[CH:29][CH:28]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].N(Cl)=O>ClCCl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: O=NCl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3[C@H](NC(=O)COc4ccccc4)C(=O)N23)cc1
Reaction time: 0.83 h
Yield: 50.6 %

Procedure:
3-Methyl-7β-phenoxyacetamidoceph-3-em-4-carboxylic acid (3.48 g., 10 m. moles) was dissolved in dichloromethane (50 ml) with p-methoxy-benzylamine (3.43 g., 25 m. moles) together with anhydrous sodium sulphate (5 g) and potassium carbonate (6.7 g). Nitrosyl chloride (12.5 ml, 10% solution in dichloromethane, 25 m. moles) was added over about 10 minutes at -5° with vigorous stirring. Some partial gel formation occurred but this dissolved while the mixture was stirred for a further 50 minutes while warming towards ambient. The reaction mixture was worked up as described in Example 7 and the organic residue crystallised from hot isopropanol (25 ml) to give the title compound (2.38 g., 50.6% yield based on the input acid) m.pt. 151° - 152°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:8]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.O>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:8]3[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]3)[CH:25]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(COCCOCCOC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCc1cc(C(=O)O)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 130 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF and 5 ml of water 3 ml of a 1M NaOH were added and the reaction mixture was stirred for 3 h at RT. Then the mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml water. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]O)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][F:7])[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred solution of diethylaminosulfur trifluoride (0.32 mL, 0.393 g, 2.44 mmol) in DCM (2 mL) at −78° C. under nitrogen was added a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.651 g, 2.03 mmol) in DCM (6 mL). Mixture was stirred at −78° C. for 0.5 h then at 20° C. for 3 h. Mixture was poured into saturated aqueous sodium hydrogen carbonate (100 mL) and ice (20 g) then extracted with DCM (3×50 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in 40-60 petroleum ether) gave the title compound (0.393 g) as an oil. MS: [M+H]+=323.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=1[CH:16]=[O:17])(=O)=O.[CH:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26]2)([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:24]=3)[CH:29]=2)=[C:8]([CH:9]=1)[CH:16]=[O:17])([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Reactant: CC(C)c1ccc2cc(B(O)O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccc(-c2ccc3cc(C(C)C)ccc3c2)c(C=O)c1
Yield: 70 %

Procedure:
Under an atmospheric argon gas flow, 2-hydroxy-5-isopropylbenzaldehyde in an amount of 4.4 g (27 mmol), trifluoromethane sulfonic acid anhydride in an amount of 11.2 g (40 mmol), pyridine in an amount of 6 milliliter (80 mmol) and dichloromethane in an amount of 100 milliliter were placed into a three necked-flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was stirred at the room temperature for 2 hours. After the reaction terminated, the resultant was separated by filtration, and after washing the resultant crude product with the use of hexane and dichloromethane, the resultant solution was vacuum dried at a temperature of 50° C. for 8 hours and as a result, 6.0 g of 2-formyl-4-isopropylphenyltrifluoromethanesulfonate (white crystal) was obtained (yield: 75%). Subsequently, under an atmospheric argon gas flow, 2-formyl-4-isopropylphenyl trifluoromethanesulfonate in an amount of 5.9 g (20 mmol), 6-isopropylnaphthalene-2-boronic acid in an amount of 4.7 g (22 mmol), (tetrakistriphenylphosphine)palladium in an amount of 1.1 g (1 mmol), 2N sodium carbonate aqueous solution in an amount of 30 milliliter and dimethoxyethane in an amount of 40 milliliter were placed into a three necked-flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was refluxed under heating for 8 hours. After the reaction terminated, adding water in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=60/40), and as a result, 4.4 g of an aimed compound (white crystal) was obtained (yield: 70%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH:21]([CH3:23])[CH3:22])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20].B(Br)(Br)Br.C1CCCCC=1>>[F:20][C:15]1[C:14]2[C:19](=[C:11]([C:4]3[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=3[OH:2])[N:12]([CH:21]([CH3:23])[CH3:22])[N:13]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2C(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc2c(F)cccc2c1-c1ccc(O)cc1O
Yield: 36.5 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-7-fluoro-2-isopropyl-2H-indazole (0.07 g, 0.22 mmol), boron tribromide (0.12 mL, 1.2 mmol) and 1.0 mL of cyclohexene to give the product (0.023 g) as a white solid.
Reaction SMILES: CC(O)=O.Cl.[CH3:6][NH:7][CH3:8].[CH:9]([C:11]1[CH:50]=[CH:49][C:14]([CH2:15][CH:16]([NH:24][C:25](=[O:48])[CH2:26][CH:27]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:6][N:7]([CH2:9][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([NH:24][C:25](=[O:48])[CH2:26][CH:27]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:36])=[O:37])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:49][CH:50]=1)[CH3:8]
Reactant: O=Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
1 ml of AcOH and 0.129 g of dimethylamine hydrochloride are added to a solution of 0.830 g of the compound obtained in step A of Example 17 in 10 ml of DCM, followed by portionwise addition of 0.456 g of sodium triacetoxyborohydride, and the mixture is stirred for 18 hours at RT. The reaction mixture is diluted with DCM, the organic phase is washed with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a chloroform/MeOH mixture (95/5; v/v). 0.52 g of the expected product is obtained.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Cl:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1CNCCc2cc(OC)c(Cl)cc21
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.421 g, 1.25 mmol) in methanol (30 mL) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.241 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H), 2.91 (s, 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 0.93 (dd, J=8, 8 Hz, 3H). MS calculated for C13H18cINO+H: 240, observed: 240.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][CH2:25][NH2:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][CH2:25][NH:26][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCCN)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)N1CCC(NS(=O)(=O)CCCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [3-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-amide was prepared by an analogous procedure as described in example 5 iii) starting from 120 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 195 mg (0.74 mmol) 3-amino-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [3-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:33])[C:23]=2[C:22](F)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:33])[C:23]=2[C:22]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=c1c2ccccc2sc2c(OCc3ccccc3)ccc(F)c12
Solvent: c1ccncc1
Product: COc1ccc(CNc2ccc(OCc3ccccc3)c3sc4ccccc4c(=O)c23)cc1
Temperature: 140 °C
Yield: 100.2 %

Procedure:
To a solution of 4-methoxybenzyl amine (1.63 g, 11.89 mmol) in dry pyridine (10 ml) was added 4-Benzyloxy-1-fluoro-thioxanthen-9-one (1 g, 2.97 mmol) in a single portion. The mixture was then heated to reflux (140° C.) for 18 hrs. The resulting hot orange suspension was allowed to cool to room temperature before being poured onto 100 ml of crushed ice. The precipitate was filtered off and washed with copious amounts of water to give the title compound as a red/orange solid (1.35 g, 89.6%). m/z (LC-MS, ESP): 454 [M+H]+ R/T=6.09 mins.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH-].[Na+].COC1C=CC(O)=CC=1>>[C:8]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCC(=O)O
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)NCCCC(=O)O

Procedure:
The general procedure above is utilized with 51.5 g (0.5 mol) of 4-aminobutyric acid, 52.39 (0.5 mol) of methacryloyl chloride, 40 g (1 mol) of sodium hydroxide. p-methoxyphenol is used as an inihibitor. Crystallization from ethyl acetate yielded very low melting crystalline material, melting point (30°-35° C.). Purity by bromination 100.14%. NMR (CDCl3), 10.85 gamma (br s, 1H, COOH), 7.1 gamma (br s, 1H, NH), 6.0 gamma (br s, 1H, =CH2), 5.65 gamma (br s, 1H, =CH2), 3.6 gamma (q, 2H, NCH2), 2.6 gamma (t, 2H, CH2CO), 2.2 gamma (br s, 5H, CH3 and CH2CH2CH2).
Reaction SMILES: [C:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-tert-butyl diethanolamine (16.4 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a non-isolable amount of product within a mixture of oligomeric diethanolamines.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.[ClH:24].C(N=C=NCCCN(C)C)C.[NH2:36][CH2:37][CH2:38][N:39](C(OC(C)(C)C)=O)[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>C(#N)C.C(OCC)C.C(O)C.C(N(CC)CC)C>[ClH:24].[ClH:24].[C:43]1([CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37][NH:36][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(CCN)CCCc1ccccc1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NCCNCCCc1ccccc1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.09 g (ca 3.2 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.15 g (10 mM) of N-hydroxysuccinimide in acetonitrile (15 ml) was added 1.92 g (10 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature, and the mixture was stirred for 2 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide a crude active ester (1.63 g). To a solution of this crude active ester (1.63 g) and 1.4 ml (10 mM) of triethylamine in acetonitrile (15 ml) was added 1.67 g (6.00 mM) of tert-butyl N-(2-aminoethan-1-yl)-3-phenylpropan-1-ylaminocarboxylate at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude residue was subjected to column chromatography (methanol/ethyl acetate 10%), whereby a crude product (2.13 g, containing impurities) was obtained. To 413 mg (0.80 mM) of this crude product was added 1.5 ml (18 mM) of 12N-hydrochloric acid, and the mixture was stirred for several minutes. Then, ethanol and diethyl ether were added to the reaction mixture and the resulting crystals were collected by filtration and rinsed serially with ethanol, acetone, and diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[K+]>C(O)C.CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen protection, to a 500 mL flask were added 16.6 g (0.1 eq.) metformin hydrochloride solid and 100 mL ethanol solvent, and the reaction was stirred under mild heating until the solid was completely dissolved, then was cooled to ambient temperature. To the reaction was added 105 mL (0.105 eq.) 1N potassium hydroxide in methanol, and stirred while the reaction temperature was controlled at no more than 40° C. After 1 hr, about 150 mL solvent was removed under reduced pressure prior to slowly cool to about 10° C., then precipitation was initiated. The reaction was suction filtered, the precipitate was washed 2× by fresh ethanol, and the filtrates were combined to give the free base of metformin in ethanol.