Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of valeryl chloride (13.3 mL, 112 mmol) in dichloromethane (35 mL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (100 mL), and the reaction was stirred overnight at room temperature and then stirred for one hour with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to provide 11.1 g of N-(4-chloroquinolin-3-yl)pentanamide as a light brown solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([Cl:6])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Chloroacetic acid chloride (0.69 ml; 8.44 mmol) is dropped slowly into a stirred solution of 4-chloro-3-trifluoro methyl aniline (1.5 g; 7.67 mmol) in pyridine (0.81 ml; 9.97 mmol) and dichloromethane (15 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.05 g (98%) brownish solid of 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25](=[O:27])[CH3:26].C(C1C=CC=CC=1)(=O)C>CN(C=O)C>[Cl:21][C:20]1[C:15]([S:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[N:7]=2)=[C:16]([C:25](=[O:27])[CH3:26])[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: Sc1nc2cc(Cl)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a 0.55M solution of 5-chloro-2-mercaptobenzothiazole, obtained from Aldrich, (5.55 g, 27.5 mmol) in DMF at ambient temperature was added NaH, 60% oil dispersion obtained from Aldrich, (1.2 g, 30.0 mmol) portionwise followed by 1-(2,3-Dichloro-5-nitro-phenyl)-ethanone (248) (5.83 g, 25 mmol). The reaction solution turned from bright orange to deep red upon acetophenone addition and was heated to 60° C. for 1 hour. The mixture was allowed to cool for a couple of minutes and the product was precipitated out of solution by the slow addition of H2O (250 mL). After 1 h of stirring the product was collect by vacuum filtration using a buchner funnel, dried under a stream of air for 3 h, and triterated with a 1:1 MeOH/CH2Cl2 solution (200 mL) to yield 5.2 g (52%) of 251 as an orange solid. An additional 3.77 g (39%) could be isolated by purifying the mother liquor using column chromatography (dry load, 100% CH2Cl2).
Reaction SMILES: [P:1](Cl)(Cl)(=[O:13])[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:32][C:33](=[O:37])[C@H:34]([CH3:36])[NH2:35])[C:28]([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.[F:45][C:46]1[C:51]([OH:52])=[C:50]([F:53])[C:49]([F:54])=[C:48]([F:55])[C:47]=1[F:56]>ClCCl>[C:3]1([O:2][P:1]([NH:35][C@@H:34]([CH3:36])[C:33]([O:32][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])([O:52][C:51]2[C:46]([F:45])=[C:47]([F:56])[C:48]([F:55])=[C:49]([F:54])[C:50]=2[F:53])=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@H](N)C(=O)OCC(C)(C)C
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NP(=O)(Oc1c(F)c(F)c(F)c(F)c1F)Oc1cccc2ccccc12)C(=O)OCC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
α-Naphthyl phosphorodichloridate (10.0 g, 38.46 mmol) was dissolved in 40 mL of dry dichloromethane and subsequently cooled to 0° C. After addition of solid (L)-alanine neopentyl ester p-toluenesulfonic acid salt (12.7 g, 38.46 mmol), the reaction mixture was cooled to −70° C. and then treated with triethylamine (11.2 mL, 77.0 mmol) dissolved in 50 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0° C. Subsequently, a preformed solution of pentafluorophenol (7.07 g, 38.46 mmol) and triethylamine (5.9 mL, 42.32 mmol) dissolved in 20 mL of dry DCM was added over 5-10 min and was continued stirring for additional 2 h. The solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in 50 mL of TBME and stirred for 10 min at room temperature. Subsequent filtration removed more triethylamine hydrochloride and yielded a filtrate that was again stripped of its solvent under reduced pressure. Column chromatography (dichloromethane) yielded the desired product (14.7 g, 72% yield) as solid diastereomeric mixture.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:16]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:15]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1>C(OCC)(=O)C.O>[CH:24]1([CH2:23][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)=[N:15][C:16]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Yield: 101 %

Procedure:
Sodium carbonate (3.25 g, 30.6 mmol) and tetrakis triphenylphosphine palladium (0.59 g, 0.51 mmol) were added to a 1,4-dioxane (60.0 ml)-water (30.0 ml) mixture solution of 2-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purine (3.0 g, 10.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2.5 g, 11.2 mmol) at room temperature and the resulting mixture was heated to reflux for 3 hours in an argon atmosphere. The reaction mixture was left standing to cool and then poured into water, and ethyl acetate was added to separate the layers. The solid precipitated in the aqueous layer was collected by filtration, washed with water, and dried at 50° C. under reduced pressure to give the title compound (3.63 g, 100%) as a white solid.
Reaction SMILES: P([O-])([O-])(O)=O.[Na+].[Na+].O.[C:9]([OH:21])(=[O:20])[CH2:10][C:11](CC(O)=O)([C:13]([OH:15])=[O:14])O.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)C[N:28](C)[C@H](C)[C@@H](O)[C@@]1(O)C>O>[NH2:28][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]([OH:21])=[O:20]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
To water (80 mL) agitated at 15° C. to 25° C., disodium hydrogenphosphate 12 hydrate (3.3 g) and citric acid monohydrate (0.44 g) were added. After these buffers were completely dissolved, azithromycin (1.0 g) was added and dissolved with agitation. After confirming that the solution became clear, sterile purified water was added to prepare 100 mL of the azithromycin-containing aqueous pharmaceutical composition (Comparative Example 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2([C:30]#N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1)C1C=CC=CC=1>O1CCCC1.BrCCBr>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2([C:30]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To bromobenzene (0.6 g) and magnesium turnings (0.2 g) in 30 ml dry tetrahydrofuran under nitrogen was added a small crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature, 1-benzyl-4-(1-cyanocyclohexyl)piperazine (1 g) was added. After 23 hours, the reaction was filtered, 20 ml saturated aqueous ammonium chloride was added and the mixture was extracted with diethyl ether. The ether was dried and removed in vacuo. The residue was chromatographed on silica gel eluted with chloroform to yield pure 1-benzyl-4-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]([F:13])([CH2:10][CH2:11][OH:12])C(OCC)=O.CC[O:16][CH2:17][CH3:18]>>[CH3:1][C:17]([OH:16])([CH3:18])[C:4]([F:13])([F:3])[CH2:10][CH2:11][OH:12]
Reactant: [Li]C
Reactant: CCOC(=O)C(F)(F)CCO
Reactant: CCOCC
Product: CC(C)(O)C(F)(F)CCO
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 311 mL of 1.6M ethereal methyllithium (0.498 mol) of 0° was added dropwise 11.16 g (0.066 mol) of ethyl 2,2-difluoro-4-hydroxybutanoate in 150 mL of ether. The mixture was stirred at 0° C. for 1 hr and at 25° C. for 17 hr. The mixture was quenched by adding 14 mL of saturated brine at 0° C. The mixture was poured into saturated brine and the product was isolated with ether. The ether layers were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed on 0.06-0.20 mm of silica gel to give 4-methyl-3,3-difluoro-1,4-pentanediol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(N(CC)CC)C.C(Cl)(=O)OCC.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1>C(Cl)Cl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:46])=[CH:43][CH:42]=1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(Oc3ccccn3)cc2)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of ethyl 2-[(3-aminomethyl-4-methoxyphenyl)-methyl]butyrate hydrochloride (302 mg, 1.00 mmol) [Japanese Patent Application No. 2000-158424] and triethylamine (390 μL, 2.80 mmol) in 10 mL of dehydrated methylene chloride was added ethyl chlorocarbonate (105 μL, 1.10 mmol) under cooling with ice and stirring, and the mixture was stirred for 20 minutes under cooling with ice. Next, 4-(2-pyridyloxy)benzoic acid (237 mg, 1.10 mmol) was added and the mixture was stirred for 1 hour under cooling with ice and for 5 hours at room temperature. Methylene chloride was added to the reaction mixture, which was washed with water, brine, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:2 v/v) to obtain 317 mg (68%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]=[N:7][OH:8].[F:13][C:14]1[C:15]([NH2:24])=[N:16][C:17](S(C)(=O)=O)=[N:18][CH:19]=1>O1CCCC1>[NH2:24][C:15]1[C:14]([F:13])=[CH:19][N:18]=[C:17]([O:8][N:7]=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[N:16]=1
Reactant: CS(=O)(=O)c1ncc(F)c(N)n1
Reactant: ON=Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(ON=Cc2ccccc2Cl)ncc1F
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a suspension of 60% NaH (0.063 g, 1.57 mmol) in anhydrous tetrahydrofuran (THF; 5 mL) was added in portions a solution of 2-chlorobenzaldehyde oxime (0.254 g, 1.64 mmol in 1 mL of THF) at room temperature, and the resulting frothy mixture was stirred for 1 h. To the resulting tan mixture was added 5-fluoro-2-methanesulfonylpyrimidin-4-ylamine (0.25 g, 1.31 mmol), at which point the reaction mixture turned orange and most of the solids dissolved. Within minutes of the addition a new solid had precipitated, and the resulting orange mixture was stirred at room temperature for 16 h. The entire reaction mixture was adsorbed to Celite (2.5 g) and the adsorbed material was purified by flash chromatography (24 g SiO2; 0→100% EtOAc/hexanes) to give 2-chlorobenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.173 g, 50%) as a white solid: mp 220-230° C. dec; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.05 (d, J=3.1 Hz, 1H), 7.92 (dd, J=7.8, 1.5 Hz, 1H), 7.54 (m, 5H); ESIMS m/z 267 ([M+H]+), 265 ([M−H]−).
Reaction SMILES: Cl[CH:2](Cl)[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7].[OH-:12].[Na+].[ClH:14]>O>[Cl:14][CH:3]([CH:2]=[O:12])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cl
Reactant: [OH-]
Reactant: CC(C)(CC(=O)O)CC(Cl)Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(CC(=O)O)C(Cl)C=O

Procedure:
30 g of 5,5-dichloro-3,3-dimethylpentanoic acid and 18 g of NaOH, dissolved in 20 ml of water, are metered simultaneously into 60 ml of water while the pH is monitored, the metering being carried out at a rate such that the pH is 9-10 during the reaction. As soon as the pH value remains constant, the reaction is complete. The reaction mixture is brought to pH 3 with hydrochloric acid, and is extracted with dichloromethane. 20.9 g of 4-chloro-3,3-dimethyl-5-oxo-pentanoic acid of boiling point 110°-115° C./0.09 are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:20]1[S:21][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)=[CH:18][CH:19]=1)(=[O:23])=[O:24]
Reactant: COc1cccc(-c2ccc(S(=O)(=O)Cl)s2)c1
Reactant: Cc1noc(N)c1Br
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)c1
Yield: 48 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) give a solid.
Reaction SMILES: [Li][C:2](C)(C)[CH3:3].CCCCC.[C:11]1([S:17]([N:20]2[C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:28]=[C:23]3[CH:22]=[CH:21]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(I)C>C1COCC1>[C:11]1([S:17]([N:20]2[C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:28]=[C:23]3[CH:22]=[C:21]2[CH2:2][CH3:3])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(F)c3)cnc21
Solvent: CCI
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1cc2cc(-c3cccc(F)c3)cnc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
1.7 M solution of t-BuLi in pentane (0.71 mL, 1.20 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of 12 (352.0 mg, 1.00 mmol) in THF (2.0 mL). The mixture turned red-brown. After the addition, the mixture was stirred for 30 min at −78° C. Neat EtI (150 μL, 1.88 mol) was added in one portion, and the mixture was allowed to reach 0° C. over a period of 1 h 15 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The mixture was then extracted with AcOEt (3×3 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated and purified by SGC with hexane:AcOEt as eluent in gradient to afford 13 (138.5 mg, 36%) as white solid. 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J=7.3 Hz, 3H), 3.21 (qd, J=7.3, 1.2 Hz, 2H), 6.39 (t, J=1.2 Hz, 1H), 7.07 (dddd, J=8.4, 8.0, 2.5, 1.0 Hz, 1H), 7.25 (ddd, J=9.9, 2.5, 1.7 Hz, 1H), 7.34 (ddd, J=7.7, 1.7, 1.0 Hz, 1H), 7.42 (ddd, J=8.0, 7.7, 5.9 Hz, 1H), 7.46-7.51 (m, 2H), 7.54-7.60 (m, 1H), 7.86 (d, J=2.2 Hz, 1H), 8.15-8.19 (m, 2H), 8.57 (d, J=2.2 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:24])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([S:46]([NH:1][CH2:2][CH:3]([C:11]2([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[O:24])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:48])=[O:47])=[CH:44][CH:45]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC1(C(CN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C(=O)OC(C)(C)C)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A cold (0° C.) solution of tert-butyl α-(1-aminomethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (337 mg, 0.867 mmol) in dry CH2Cl2 (3 mL) is treated with diisopropylethylamine (240 μL, 1.30 mmol) and 4-methoxybenzenesulfonyl chloride (215 mg, 1.30 mmol). The solution was allowed to slowly warm to room temperature, stirring overnight under N2. After diluting with CH2Cl2 (25 mL), the solution is washed with dilute NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 460 mg of a yellow oil. The oil was purified by silica gel chromatography (20 g SG; 25% EtOAc/hexane) to provide 383 mg (79%) of the desired material as a white amorphous solid:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:33])[CH2:12][N:13]1[CH2:18][C:17]2[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([O:27]C(C)(C)C)=[O:26])[CH:21]=[N:22][C:16]=2[NH:15][C:14]1=[O:32])[CH3:9].[Cl:34]CCl>>[ClH:34].[CH2:8]([O:10][C:11](=[O:33])[CH2:12][N:13]1[CH2:18][C:17]2[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[CH:21]=[N:22][C:16]=2[NH:15][C:14]1=[O:32])[CH3:9]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (E)-tert-butyl 3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate (460 mg, 1.27 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After concentration to dryness, the residue was suspended in a solution of hydrochloric acid in dioxane 4N (10 mL). The resulting white precipitate was filtered and washed with diethyl ether to give the title compound (470 mg; quantitative).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:2]2[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: Oc1ccccc1S
Reactant: Clc1cnc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Sc2ncc(Cl)cn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0°, 4.0 grams (0.027 moles) of 2,5-dichloropyrimidine is added to a mixture of 3.0 grams (0.0023 mole) 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide. After stirring overnight at room temperature, 4.0 grams of 2-chloro-5-nitropyridine is added and the mixture is heated at 80° for 4 hours. The reaction mixture is then poured into excess H2O and extracted with ethyl ether (200 ml). Washing with H2O, saturated NaHCO3, brine, drying (MgSO4), and evaporation yields the crude product.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH2:15][CH2:14][N:13]1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][N:26]=1.CN(C=[O:41])C>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[N:30][C:25]([N:13]2[CH2:14][C:15]3[C:16](=[O:41])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[NH:23][C:24]=3[CH:12]2[CH:4]2[CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:3]2)=[N:26][CH:27]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(C1Cc3ccccc3O1)N(c1ncc(-c3ccccn3)cn1)C2

Procedure:
Sodium hydride (60% in mineral oil, 182 mg, 4.55 mmol) and 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carboline (16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) in DMF (30 mL, anhydrous) were stirred at room temperature for 30 min. Dry air then was bubbled through the reaction mixture for 16 h. Ethyl acetate (200 mL) was added, and the resulting mixture was washed with 10% NaCl solution, brine, and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue triturated with ethyl acetate to yield the product as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][CH2:7][CH2:8][CH:9]1[S:13][C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:23]([CH3:32])[S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])=[N:11][CH2:10]1)C.[OH-].[K+].Cl>O1CCCC1.CO.O>[CH3:32][N:23]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][C:14]([C:12]1[S:13][CH:9]([CH2:8][CH2:7][S:6][CH2:5][C:4]([OH:33])=[O:3])[CH2:10][N:11]=1)=[CH:22]2
Reactant: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CCSCC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of ethyl{[2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl]thio}acetate (60 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added, under ice-cooling, a solution prepared by dissolving potassium hydroxide (purity 85%, 20 mg) in water (0.5 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 1 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (35 mg, yield 61%) as white crystals. MS:496(MH+).