Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1.I[CH2:31][CH2:32][CH2:33][CH3:34].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:31]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2NCCCC)c1
Yield: 50.6 %

Procedure:
A solution of 200 mg (0.5 mmol, 1 eq) of methyl 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate (prepared in Example 52c) and 60 μL (0.55 mmol, 1.1 eq) of 1-iodobutane in 2 ml of dimethylformamide in the presence of 170 μL (10.5 mmol, 2.1 eq) of diisopropylethylamine is heated at 80° C. for 16 hours. The reaction medium is hydrolyzed with water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 114.8 mg of methyl 3-[2-butylamino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellow oil. Yield=51%
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][O:24][CH2:25][CH3:26])=[O:6])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]([CH3:27])([CH3:28])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-:34])=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][O:24][CH2:25][CH3:26])=[O:6])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCC(=O)NC(C)(C)Cn1c(COCC)nc2cnc3ccccc3c21
Solvent: ClCCl
Product: CCOCC(=O)NC(C)(C)Cn1c(COCC)nc2c[n+]([O-])c3ccccc3c21
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A solution of 2-ethoxy-N-{2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (998 mg, 2.60 mmol) in 20 mL of CH2Cl2 was treated with 3-chloroperoxybenzoic acid (77%, 668 mg, 2.99 mmol). After stirring for 3 h, the reaction mixture was treated with 30 mL of additional CH2Cl2 and was washed with 1% Na2CO3 solution (2×50 mL), H2O and brine. The organic portion was then dried over Na2SO4 and concentrated to give 2-ethoxy-N-{2-[2-(ethoxymethy)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (910 mg) as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](O)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: Nc1nnc(S)s1
Product: CC(=O)Nc1nnc(S)s1
Temperature: 100 °C

Procedure:
Polyphosphoric acid (190 grams) and acetic acid (406 grams) were charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and heated, with stirring, to 100° C. To this heated, stirred mixture was then added 2-amino-5-mercapto-1,3,4-thiadiazole (250 grams). Stirring was continued for an additional hour at a temperature of 120° C. The reaction mixture was then cooled to 60° C. and poured over ice. A precipitate formed which was filtered and air dried to yield the desired product 2-acetamido-5-mercapto-1,3,4-thiadiazole having a melting point greater than 290° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1>O1CCCC1.C(N(CC)CC)C.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Fc1ccc(-c2onc3ccccc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a suspension of (16) (42.6 g, 0.2 mol) in 750 ml of dry tetrahydrofuran (THF) and 20 ml of triethylamine is added 5% palladium on charcoal (6 g). The vigorously stirred suspension is flushed with hydrogen gas and stirred at room temperature under a hydrogen atmosphere until absorption of hydrogen ceases (approximately 90-90% of the molar amount; 8-10 hours). The catalyst is removed by filtration through a bed of celite, and the solvent is removed under reduced pressure. The product (16) is recrystallized from toluene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](O)[CH2:13][CH2:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCO
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCOC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a mixture of 3-phenylpropionic acid (15.0 g) and 1-butanol (8.15 g) in pyridine (30 ml) pTSA (0.100 g) is added. When the solution is homogeneous, DCC (24.8 g) is added, and the solution is stirred at room temperature for 24 h. After addition of acetic acid (10 ml) the reaction mixture is worked up as in Example 1. A 96% yield of butyl 3-phenylpropionate is obtained, b. p. 112°-3° C. (1 mm Hg) [lit. (12), 91° C. (0.3 mm Hg)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution of ethyl 4-(4-chloro-2-nitrophenyl)-4- hydroxy-2-butynoate (7.46 g, 26.3 mmoles) in dichloromethane (350 mL) cooled in an ice-bath was added manganese dioxide (26.2 g, 301.3 mmol). The reaction mixture was stirred for 20 minutes and then was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 130 minutes and then was filtered twice through a pad of CELITE™. The filtrate was purified by flash chromatography on silica gel (195 g), eluting with dichloromethane, to afford 3.80 g (51%) of the title compound as a brownish-orange oil.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH-].[Ca+2:15].[OH-]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:15].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:15].[Ca+2:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 56.666666666666664 °C

Procedure:
A calcium citrate sample was prepared by reacting 2763.8 lbs. of citric acid with 1600 lbs. calcium hydroxide (97-98% Ca(OH)2 by analysis) in the presence of 1433 gallons of water. The mole ratio of calcium hydroxide to citric acid was very slightly less than 3:2, actually 2.92:2. The citric acid (Pfizer fine granular, food grade) was mixed in a large batch tank with 675 gallons of cold water. The calcium hydroxide (Mississippi lime, hydrated lime, food code) was mixed in a separate batch tank with 75 gallons of cold water. The calcium hydroxide slurry is then pumped into the citric acid solution at a rate to deliver the entire slurry in 10-15 minutes. It is necessary to have good agitation during the entire reaction and mixing process. The remaining 83 gallons of water is used to rinse the calcium hydroxide tank and transport lines. Due to the heat of reaction, the temperature of the resultant slurry was increased from an initial value of 15° C. (60° F.) to a maximum of 57° C. (134° F.). After the reaction is complete, the batch is cooled to 80°-90° F. The final pH of this concentrated slurry (22% calcium citrate, dry basis) should fall within the range 3.8-4.6 or can be adjusted up or down using the reacting ingredients. The slurry is then dried via spray drying utilizing a rotary wheel (7600 rpm). The outlet temperature was adjusted to 225° F. and the inlet temperature was 450° F.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH:14]([OH:21])[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>O1CCCC1.CCCCCC>[CH2:23]([O:22][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH2:11][CH2:12][CH2:13][C:14]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCCC(O)N1CCOCC1)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCCC(OCc1ccccc1)c1ccc(F)cc1)N1CCOCC1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
1.8 gms of Sodium hydride was taken in 50 ml of tetrahydrofuran at 0° C., to this 5 gms of 1-(4-Fluoro-phenyl)-5-hydroxy-5-morpholin-4-yl-pentan-1-one was added under nitrogen atmosphere and maintained for about 30 minutes. To the reaction mass 3.4 gms of benzyl bromide was added at 20-25° C. and stirred for about 6 hours. Quenched the reaction mass with hydrochloric acid and stirred for about 15 minutes. Separated the layers and extracted the reaction mass with ethyl acetate. Organic layer was separated and dried over sodium sulphate. Distilled off the solvent completely and isolated the compound by adding 7 ml of toluene and 35 ml of hexane. Filtered the compound, washed with hexane and dried at 35-40° C. to get 5.6 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-1-morpholin-4-yl-pentan-1-one.
Reaction SMILES: [C:1]([C@:3]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:5][C@@H:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2].CC(C)([O-])C.[K+].[CH2:25]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>CN(C=O)C>[C:1]([C@:3]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:35][CH:36]=4)=[CH:47][CH:46]=3)=[CH:16][CH:17]=2)[CH2:5][C@@H:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2]
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(CBr)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccc(COc3ccc([C@@]4(C#N)C[C@@H]4CCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 95.1 %

Procedure:
In 10 ml of DMF was dissolved 49 mg of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane as obtained in Example 11. Thereto was added 34 mg of potassium t-butoxide, and the resulting mixture was stirred at room temperature for 70 minutes. Thereto was added dropwise a solution of 98 mg of 4-(4-octyloxyphenyl)benzyl bromide in 3 ml of DMF, and this mixture was stirred for 6 hours. Thereafter, 20 ml of 5% hydrochloric acid was added to the reaction mixture, and the resulting mixture was subjected to extraction with 50 ml of ether. The resulting organic layer was washed with water and then with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=10/1), thereby obtaining 103 mg of the desired compound in the form of white crystals.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:13][C:12]([O:25][CH2:26][CH3:27])=[C:11]([CH3:28])[N:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].C(O)(=O)C.CCOCC>C(O)C.Cl>[CH2:26]([O:25][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][C:11]=1[CH3:28])[N:8]=[CH:7][C:6]([CH:1]([OH:5])[CH2:2][CH2:3][CH3:4])=[C:15]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:27]
Reactant: CCCC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCCC(O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-butyryl-6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine (8.0 g) in absolute ethanol (200 ml) was added dropwise at 0° C. over 1 hour to a solution of sodium borohydride (2.4 g) in absolute ethanol (200 ml). The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. Glacial acetic acid was added carefully to destroy excess borohydride and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (200 ml) and extracted with dichloromethane to give a residue which was dissolved in IMS and saturated with hydrogen chloride gas. Ether was added to induce crystallisation. The mixture was filtered to give 1-[6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridin-3-yl]butan-1-ol, m.p. 120°-124° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a white solid; mp 71-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.80 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.50-2.90 (m, 5H), 2.92 (s, 3H), 3.70-3.90 (m, 2H), 4.45-4.55 (m, 1H), 6.82 (d, 1H), 7.02 (d, 3H), 7.19 (d, 1H), 7.54 (d, 2H); MS (ES) m/z 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2136.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH2:11][CH2:10]2)#[N:2].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30]Cl)=[N:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27](/[CH:26]=[CH:25]/[C:21]3[CH:20]=[CH:19][C:18]4[C:23](=[CH:24][C:15]([Cl:14])=[CH:16][CH:17]=4)[N:22]=3)[CH:28]=1)[CH2:11][CH2:10]2)#[N:2]
Reactant: N#CCCc1cccc2c1NCC2
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc2c1N(Cc1cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c1)CC2
Temperature: 85 °C
Yield: 47 %

Procedure:
A mixture of 7-(2-cyanoethyl)-2,3-dihydroindole (690 mg, 4.01 mmol), 3-[2-E-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride (product of Example 3), 1.29 g, 4.10 mmol), and potassium carbonate (1.10 g, 7.97 mmol) in DMF (100 mL), was heated in an oil bath at 85° C. for 16 hours. The mixture was cooled and diluted with water and ethyl acetate. The organic solution was separated, washed once with water, once with saturated sodium chloride solution, then dried (over sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 70% hexane/30% ether) of the resulting residue provided 850 mg (47%) of the intermediate.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14]
Reactant: NCCCNc1ccccn1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCCN(Cc1ccccc1Cl)c1ccccn1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Sodium hydride (1.32 g) was disolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.5 g) added at room temperature. 2-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After standing overnight water (200 ml) was added and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and after partitioning into ether and chloroform at pH 3.5 and 14, an oil was obtained which was further purified by HPLC (silica gel, dichloromethane then 2% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-(2-chlorobenzyl) amino]pyridine (3.44 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH2:5].[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH:5][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34]
Reactant: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
In 20 ml of dimethylformamide were dissolved 1 g of 2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester and 1.5 g of N-hydroxysuccinimide ester of benzyloxycarbonyl-L-alanine, and the solution was stirred at room temperature for 50 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium hydrogen carbonate, and dried over sodium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to give benzyloxycarbonyl-L-alanyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester as a white powder. This powder was dissolved in a mixture of 50 ml of methanol and 10 ml of acetic acid and stirred with 500 ml of palladium black in a stream of hydrogen at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried in a desiccator overnight and dissolved in 50 ml of methanol. With adjusting pH to 9-10 with 1 N sodium hydroxide, the solution was stirred at room temperature for 3 hours. This reaction mixture was adjusted to pH 5 and concentrated under reduced pressure. The residue was dried in a desiccator overnight, dissolved in 10 ml of a 30% solution of hydrogen bromide in acetic acid, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and adjusted to pH 4 with saturated sodium hydrogen carbonate. It was chromatographed on a column (200 ml) of MCI gel CHP-20P, and water to 50% aqueous methanol-water gradient elution was carried out. The eluate was concentrated under reduced pressure and lyophilized to give L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine as a white powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=C(C)[S:10][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[F:13].[ClH:14].O1CCOCC1>C(O)CO.[OH-].[Na+]>[ClH:14].[NH2:8][C:7]1[C:2]([F:1])=[C:3]([F:13])[CH:4]=[C:5]([F:12])[C:6]=1[SH:10]
Reactant: Cc1nc2c(F)c(F)cc(F)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: Nc1c(F)c(F)cc(F)c1S
Temperature: 125 °C
Yield: 73 %

Procedure:
A solution of 4,5,7-trifluoro-2-methylbenzothiazole (25.0 g, 123 mmol) in ethylene glycol (310 mL, 0.4 M) and 30% aq NaOH (310 mL, 0.4 M) was degassed using a nitrogen stream and subsequently heated to a gentle reflux (125° C.) for 3 h. The solution was cooled to 0° C. and acidified to pH 3-4 using conc. HCl (appox. 200 mL). The solution was extracted with ether (750 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4, filtered and treated with 2,2-di-tert-butyl-4-methylphenol (0.135 g, 0.5 mol %). After concentrating to dryness, the crude product was dissolved in anhyd methanol (200 mL) and treated with an HCl solution in 1,4-dioxane (37 mL, 4 N, 148 mmol). The resulting mixture was concentrated to dryness, triturated with isopropylether (100 mL) and filtered to give 2-amino-3,4,6-trifluorothiophenol hydrochloride (19.3 g, 73%) as a light brown solid that was used without further purification. mp. 121-124° C.; Rf 0.43 (30% ethyl acetate in heptane); Anal. calcd for C6H5ClF3NS: C, 33.42; H, 2.34; N, 6.50; S, 14.87. Found C, 33.45; H, 2.27; N, 6.48; S, 14.96.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([OH:10])=[N:8][O:9][C:5]=2[CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[N:8]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[O:9][C:5]=2[CH:4]=1
Reactant: Oc1noc2cc(CCl)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: O=c1c2ccc(CCl)cc2on1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 75 mL of methylene chloride, 5.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol was suspended, and to this was added 0.137 g of pyridinium p-toluenesulfonic acid and 2.98 mL of 3,4-dihydro-2H-pyran. This was stirred for 8 hours at room temperature. To the reaction mixture was added 30 mL of water and an organic layer was separated. An aqueous layer was extracted with 10 mL of methylene chloride, and this along with the organic layer was washed with an aqueous saturated sodium chloride solution and dried with anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and 20 mL of diisopropyl ether was added to the obtained residue. A seed crystal was added and, after 30 minutes of stirring at room temperature, solids were filtered to obtain 6.65 g of 6-(chloromethyl)-2-(tetrahydro-2H-pyran-2-yl)-1,2-benzisoxazol-3(2H)-one in the form of a pale yellowish-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[CH3:30][O:31]C1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:31][CH3:30])=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: COc1ccc(-c2ccc(Br)cc2S(C)(=O)=O)cc1
Yield: 73 %

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 4-methoxyphenylboronic acid, the title compound was obtained as a brown solid in 73% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.