Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:36])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]([CH3:35])[CH3:34])(=O)C.C(Cl)(C)=O>CC(O)=O>[Cl:36][C:22]1[N:21]=[C:20]2[C:25]([NH:26][CH:27]=[N:19]2)=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]([CH3:35])[CH3:34])[N:23]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4C(C)C)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(C)c1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 20 h
Yield: 45.1 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-isopropylimidazol-1-yl)purine (2.96 g, 5.7 mmol, contaminated with 2-isopropylimidazole) was dissolved in HOAc (190 mL). To the solution was added AcCl (1.9 mL, 2.10 g, 26.7 mmol), and the mixture was stirred at 65° C. for 20 h in a sealed flask (reaction was complete, TLC). Volatiles were evaporated in vacuo, and the residue was washed (CH2Cl2) and dissolved in 0.1 N NaOH/H2O (200 mL). Precipitation with CO2 gave 2-chloro-6-(2-isopropylimidazol-1-yl)purine (0.675 g, 54%). This solid was washed (boiling MeOH/iPrOH) to give the title compound (0.60 g, 48%): mp 268-268.5° C.; UV (MeOH) max 213, 254, 288 nm (∈ 26 100, 4600, 13 100), min 239, 257 nm (∈ 3700, 4600); 1H NMR (500 MHz, DMSO-d6) δ 14.06 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 7.07 (d, J=1.6 Hz, 1H), 3.93 (br s, 1H), 1.29 (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 156.4, 154.3, 151.0, 146.5, 145.8, 127.9, 122.0, 120.4, 27.7, 21.6; HRMS m/z 285.0626 (MNa+[C11H11ClN6Na]=285.0631). Anal. Calcd for C11H11ClN6: C, 50.29; H, 4.22; N, 31.99. Found: C, 50.12; H, 4.27; N, 32.16.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 4-benzyloxy-3-nitro-benzoic acid (36 g, 132 mmol) in toluene (1000 mL) and dimethylformamide (3 mL) was treated with thionyl chloride (47 g, 28.7 mL, 395 mmol) and stirred at 90° C. for 18 hours. The volatiles were evaporated completely and the residue dried under high vacuum. 4-Benzyloxy-3-nitro-benzoyl chloride thus obtained (37.5 g, 97%) was used crude in the following reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)=[O:42]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COC(=O)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg), 4-methoxycarbonylphenyl borate (191 mg) and potassium carbonate (266 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:2→1:1) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (290 mg).
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:6])=[O:5].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>CO>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:6]
Reactant: CN1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 89.4 %

Procedure:
To a solution of 1.2 gm (21.4 mMol) potassium hydroxide in 12 mL methanol was added 1.0 gm (4.76 mmol) 5-methanesulfonylamino-1H-indole followed by 0.76 mL (6.2 mMol) 1-methyl-4-piperidone. The homogeneous solution was heated to reflux for 18 hours under nitrogen. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution adjusted from 14 to 8-9 by the addition of acid. The precipitate that formed was filtered, washed with water and dried under vacuum to give 1.3 gm (89.6%) of the title compound as a tan solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nccn2c(Br)cnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: NS(=O)(=O)c1ccc(CNc2nccn3c(Br)cnc23)cc1
Temperature: 108 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a solution of 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (2 g, 8.6 mmol) in iBuOH (5 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (2.1 g, 9.5 mmol) and DIPEA (3.7 ml, 21.5 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a white solid (1.24 g, 38%)
Reaction SMILES: [OH:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3](=[CH2:6])[C:4]#[N:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O.C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[O:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3]([C:4]#[N:5])=[CH2:6])[CH3:21]
Reactant: C=C(C#N)C(O)C(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C#N)C(OC(=O)OCC)C(C)C
Yield: 95.5 %

Procedure:
A nitrogen-purged 5 L, three-necked, round-bottom flask with overhead stirring is charged with 150 g (1.2 mol) of 3-hydroxy-4-methyl-2-methylenepentanenitrile, 1.0 L of methylene chloride, and 170 mL (2.1 mol) of pyridine. The solution is cooled at 10° C. to 15° C. in an ice bath. Using a 1 L graduated addition funnel, a mixture of 0.5 L of methylene chloride and 200 mL (2.1 mol) of ethyl chloroformate is added slowly while maintaining the reaction temperature at 20° C.±5° C. The reaction is stirred at 22° C.±3° C. for about two additional hours. The reaction solution is poured into a 6 L separatory funnel containing 200 mL (2.3 mol) of hydrochloric acid and 1.25 L of water. The lower organic layer is washed again with a solution of 60 mL (0.7 mol) of HCl and 0.5 L of water. The organic layer is dried over anhydrous magnesium sulfate (30 g), filtered, and concentrated by rotary evaporation to provide 226 g of carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester as a yellow oil which may be used in the next step without further purification. Acetic acid 2-cyano-1-isopropyl-allyl ester (using acetyl chloride)
Reaction SMILES: C(C1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=1)#N.O.[C:24]([OH:27])(=[O:26])[CH3:25]>Cl.C(Cl)(Cl)Cl.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=[C:25]([C:24]([OH:27])=[O:26])[CH:8]=1
Reactant: COc1cc(C#N)nc(Oc2c(Cl)cccc2C(F)(F)F)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(Oc2c(Cl)cccc2C(F)(F)F)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-cyano-4-methoxy-6-[2-chloro-6-(trifluoromethyl) phenoxy] pyridine (2.88 g, 0.0088 mol) was suspended in about 20 ml of concentrated hydrochloric acid and about 10 ml of acetic acid. The obtained suspension was stirred at about 100° C. for about 4 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in chloroform-water. The obtained solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][C:21]([C:24]([O:26]C)=[O:25])=[N:22][OH:23])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:1]([C:3]1([CH2:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][OH:23])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(=NO)C(=O)OC)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1(CC(=NO)C(=O)O)CCCN2CCc3c([nH]c4ccccc34)C21
Yield: 81 %

Procedure:
A mixture of 9.25 g. (0.025 mole) of (+)-ethyl-1-(2'-methoxycarbonyl-2'-hydroxyimino-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine, 8.0 g (0.2 mole) of solid sodium hydroxide, 100 ml. of ethanol and 5.0 ml. of water is acidified to a pH value of 6.3 by the addition of a solution of 16 g. of citric acid in 150 ml. of water. The solution is extracted six times with 50 ml. of dichloromethane each. The united organic phases are extracted with a saturated sodium chloride solution, the layers are separated, the organic phase is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. To the residue 50 ml. of ether are added, the mixture is heated to boiling, then cooled, the precipitated product is filtered and dried. Thus 7.2 g. of the named compound are obtained, yield 81%. Mp.: 124° C. (decomposition).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>CC(C)=O.CCOCC>[C:20]([O:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)(=[O:23])[CH:21]=[CH2:22]
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CC(=O)Oc1ccc(C)cc1-n1nc2ccccc2n1
Yield: 67.7 %

Procedure:
Into a flask provided with a magnetic stirrer is added 10.0 g of 2-(2H-benzotriazol-2-yl)-4-methylphenol dissolved in 350 ml acetone. Then 10% NaOH is added dropwise until the pH is 9. With stirring, 4.1 g of acryloyl chloride is added dropwise while maintaining the pH between 7 and 9 by addition of dilute base. After the addition is complete, the solvent is evaporated leaving a yellow residue which is dissolved in 80 ml ether and extracted with an equal volume of 5% NaOH solution until the aqueous washings are colorless. After evaporation of the ether, there is left 8.4 g of a yellow residue as the product, whose structure, is confirmed by NMR. The yield is 67.7%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>CC(O)=O>[BrH:10].[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ncccc1CO
Solvent: CC(=O)O
Product: Br
Product: Nc1ncc(Br)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.9 %

Procedure:
To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (156 g, 1.257 mole) in HOAc (2.5 L) at ambient temperature was added bromine (64.1 mL, 1.257 mole) dropwise over 1 hr. A suspension began to form during the addition. An exotherm to 36° C. was controlled with an ice bath. After the addition, the reaction mixture was stirred at ambient temperature overnight. The yellow precipitate was filtered, washed with ether and air-dried to give the title compound (289 g, 81%): MS (ES) m/e 203.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6, free base) δ 7.89 (d, J=2.3 Hz, 1H), 7.52 (s, 1H), 5.92 (br s, 2H), 5.29 (br s, 1H), 4.30 (s, 2H).
Reaction SMILES: [Cl-].[NH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][NH3+:13])=[O:4].[OH:14][C:15]1[C:16]([C:31](O)=[O:32])=[N:17][C:18]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>>[NH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][NH:13][C:31]([C:16]1[C:15]([OH:14])=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[N:23]2)=[C:18]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:17]=1)=[O:32])=[O:4]
Reactant: NC(=O)c1cc(F)ccc1C[NH3+]
Reactant: CN(c1nc(C(=O)O)c(O)c2ncccc12)S(C)(=O)=O
Agent: [Cl-]
Product: CN(c1nc(C(=O)NCc2ccc(F)cc2C(N)=O)c(O)c2ncccc12)S(C)(=O)=O

Procedure:
In a similar manner as described for Example 7, Step 3, [2-(aminocarbonyl)4-fluorophenyl]methanaminium chloride (from Example 9, Step 3) was coupled with 8-hydroxy-5-[methyl(methylsulfonyl)amino]-1,6-naphthyridine-7-carboxylic acid (from Example 5, Step 3) to afford the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]N(CCN(C)C)C.[Li]C(CC)C.S(OC)(OC)(=O)=O>CCOCC.O>[C:1]([N:8]1[CH:13]([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: O
Product: CCC1CCCC(C)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of N-Boc-2-ethylpiperidine (1.5 g, 7.0 mmol) in 28 mL of ether was cooled to −60° C. and treated with TMEDA (1.6 mL, 10.85 mmol), followed by sec-BuLi (8.5 mL, 10.85 mmol) dropwise. The mixture was slowly warmed to −20° C., stirred for 30 min, and then cooled to −78° C. The mixture was treated with a solution of dimethyl sulfate (1.6 mL, 16.69 mmol) in ether and slowly warmed to room temperature. The mixture was diluted with water and then extracted with ether. The combined extracts were dried over K2CO3 and concentrated to give a crude product as an oil which was chromatographed on silica with 5% EtOAc/hexane to give 0.88 g (59%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 3.91-3.87 (m, 1H), 3.69-3.65 (m, 1H), 1.83-1.41 (m, 17H), 1.21-1.19 (d, 3H), 0.85-0.82 (t, 3H); 13C NMR (62.7 MHz) 155.2 (s), 78.6 (s), 53.0 (s), 46.8 (s), 28.5 (s), 27.2 (s), 26.7 (s), 22.4 (s), 20.7 (s), 13.4 (s), 11.4 (s) ppm.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[C:1]1([C:7]2([CH2:12][O:13][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 16 h
Yield: 83.16 %

Procedure:
To a stirred solution of (1-phenyl-cyclopentyl)-methanol] (278) (10 g, 56.73 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.47 mmol) followed by mesyl chloride (5.3 mL, 68.08 mmol) at 0° C. Stirring was continued at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The separated organic fraction was dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (279) (12 g, 83.16%) as a yellow semi-solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:8]([S:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]2OCO[C:19]=2[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:9])([OH:7])=O.[CH3:26]COCC>N1C=CC=CC=1>[CH3:9][C@@H:8]1[S:10][C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[CH:21][C:22]=2[C:5]1=[O:7]
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SC(C)C(=O)O
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1Cc2ccc(C)cc2C(=O)[C@H](C)S1
Temperature: 25 °C
Yield: 62 %

Procedure:
Thionyl chloride (16.4 g) and pyridine (3 drops) were successively added dropwise to a solution of methyl 2-(1-carboxyethyl)thio-3-(3,4-methylenedioxyphenyl)propionate (26.0 g) in ether (250 ml), followed by stirring for an hour at room temperature and for an hour under reflux. The mixture was concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (50 ml) and the resultant solution was added dropwise to a mixture of aluminum chloride (AlCl3)(27.0 g) and dichloromethane (200 ml) under ice-cooling. After stirring for two hours under ice-cooling, the mixture was poured into ice-water. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The residual oil was dissolved in methanol (250 ml), to which a solution of sodium methoxide in methanol (28%, 10 ml) was added. The mixture was stirred for 1.5 hours at room temperature, to which 2N--HCl (250 ml) was added. The precipitated crystals was collected by filtration, affording methyl trans-4,7-dimethyl-5-oxo-1,2,4,5 -tetrahydro-3-benzothiepine-2-carboxylate (15.0 g, 62%). Recrystallization from ethyl acetate-hexane gave colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CCCNC(=O)c1ccc(Cl)cc1O
Temperature: 50 °C
Yield: 97.2 %

Procedure:
A 22 L, five neck round bottom flask, was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Reagent acetone (13000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was pumped through a warm pressure filter dressed with Whatman #1 paper into a clean 22 L reactor. The clear yellow filtrate was heated to 50° C. while stirring. Sodium hydroxide solution (50% aqueous; 155 g, 1.94 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (60° C.) for 2.5 hours and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and dried in a vacuum oven at 50° C. for 24 hours to give 527.3 g of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate as an off-white solid. Using acetone in the final stage of the synthesis always resulted in the production of the anhydrous crystalline form. The yield was 97.2%. The Form I prepared was a crystalline polymorph having a melting point onset of about 215.07° C. and characterized by an X-ray powder diffractogram substantially as shown in FIG. 1. A DSC scan, TGA spectrum, and Sorption/desorption curve of the Form I prepared are shown in FIGS. 6, 11, and 22, respectively. FTIR spectra of the Form I prepared are shown in FIGS. 16A and 16B.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][S:3]1.C1C=CC=CC=1.[Br:14][CH:15]([Br:19])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:7])[N:6]([C:16](=[O:17])[CH:15]([Br:19])[Br:14])[CH2:5][CH2:4][S:3]1
Reactant: O=C(Cl)C(Br)Br
Reactant: CC1(C)NCCS1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1(C)SCCN1C(=O)C(Br)Br

Procedure:
To a mixture of 3.5 g. of 2,2-dimethyl thiazolidine, 50 ml. of benzene and 7.1 g. of dibromoacetyl chloride mixed in an ice bath was added 3.1 g. of triethylamine dropwise with stirring and continued cooling. When reaction was complete, the mixture was poured into watwer and the benzene layer separated, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 8.5 g. of a dark oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH:11]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([CH:11]2[CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)=[CH:6][CH:7]=1)([O-:4])=[O:2]
Reactant: COC(=O)C1CC(c2ccccc2)C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1CC(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 8 h

Procedure:
Fuming nitric acid (0.54ml.) was added dropwise to a stirred solution of methyl 3-phenylcyclobutanecarboxylate (950mg.) in acetic anhydride (5ml.) and glacial acetic acid (0.25ml.) at -5° C. The reaction mixture was set aside overnight at room temperature then poured onto ice and extracted with ethyl acetate (3 × 20ml.) The ethyl acetate solution was dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on a column of "Florisil" (25g.), eluting with toluene, gave methyl 3-(4-nitrophenyl)cyclobutanecarboxylate as a pale yellow oil. The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (δ values):- ##STR16##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:13]([CH2:20][CH2:21][NH:22][C:10]([C:2]1[NH:1][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc2ncccc2[nH]1
Reactant: NCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCOc1ccccc1)c1cc2ncccc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 32, 50 mg, 0.31 mmol) in DMF (5 mL), was added 2-phenoxyethylamine (44 μL, 0.34 mmol), DIPEA (118 μL, 0.68 mmol) and HOBt (42 mg, 0.31 mmol) sequentially. The reaction mixture was stirred for 5 min prior to the addition of EDCI (42 mg, 0.22 mmol) in one portion. The resulting mixture was stirred for 20 h at rt and partitioned between ethyl acetate (50 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oil. Trituration with diethyl ether/isohexane and collection by filtration gave, after air-drying, the title compound as a cream coloured solid. δH (d6 DMSO): 3.48 (2H, m), 4.14 (2H, t), 6.94 (3H, m), 7.17 (1H, dd), 7.28 (3H, m), 7.77 (1H, d), 8.37 (1H, dd), 8.86 (1H, t); m/z (ES+)=282 [M+H]+; RT=2.60 min.