Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](N)=O)[CH:7]=1.[NH2:18]C1C=CC(O)=CC=1.ClC1C=CN=C(C)C=1>>[CH3:12][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[CH:2][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)cc1
Agent: Cc1cc(Cl)ccn1
Product: Cc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
{4-[(2-Methylpyridin-4-yl)oxy)phenyl}amine (2B) was prepared by a method analogous to that described for 4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from 4-aminophenol and 4-chloro-2-methylpyridine, MS ES: 201 (M+H)+, calcd 201, RT=1.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>C(O)C.[Cl-].[Na+].O>[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=Cc1ccccc1O)C2=O
Yield: 62.9 %

Procedure:
To a solution of 6-methoxy-1-tetralone (30 g) and 2-hydroxybenzaldehyde (25 g) in ethanol (200 ml) was added concentrated hydrochloric acid (10 ml), and the solution was refluxed for one day and one night. To the reaction solution was added brine, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-(2-hydroxybenzylidene)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one(30 g). To a solution of a portion thereof (15 g) in ethanol (200 ml) was added platinum(IV) oxide (0.1 g), and the solution was stirred overnight under a hydrogen atmosphere at ambient pressure. The reaction solution was filtered, and the solvent was evaporated in vacuo. To a solution of a portion of the resulting 2-(2-hydroxybenzyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one crude product (1.0 g) in ethylene glycol (15 ml) was added potassium hydroxide (1.2 g) and hydrazine hydrate (2 ml), and the solution was refluxed overnight. To the reaction solution was added 5N hydrochloric acid, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenol (810 mg) was used according to an analogous synthetic method to Preparation Example 80 to provide the title compound (1.1 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2s1

Procedure:
2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF (20 ml). 0.65 g (46%) of a yellow liquid was isolated.
Reaction SMILES: CN.[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1>[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([CH:9]([NH:25][CH3:24])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
2.0 M methylamine solution in THF (18 mL, 36.0 mmol) was added to a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (2.52 g, 8.93 mmol) in anhydrous THF (20 mL), The reaction mixture was stirred at room temperature for 1 h and then sodium cyanoborohydride (1.68 g, 26.79 mmol) and acetic acid (1 mL) were added. The resulting mixture was stirred at room temperature for 72 h until the starting material was consumed completely. At this point, saturated K2CO3 solution (40 mL) was added to and after stirring for 15 min, the solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over Na2SO4 and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield [1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine as an off-white solid (1.40 g, 53%), MS (ES) m/e 296[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1
Yield: 80 %

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and tert-butyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate [see preparation 52]. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (10:90) changing to (80:20) in 10% increments to afford the title compound as a clear oil, (80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][C:15]([NH2:18])=[C:14]4[O:19][C:20]([C:22]5[C:30]6[C:25](=[CH:26][N:27]=[CH:28][CH:29]=6)[S:24][CH:23]=5)=[CH:21][C:13]=34)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:40](O)(=[O:49])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:18][C:15]1[N:16]=[CH:17][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:40](=[O:49])[CH2:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:6][CH2:5]3)[CH:11]=2)=[C:13]2[CH:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][N:27]=[CH:28][CH:29]=4)[S:24][CH:23]=3)[O:19][C:14]=12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3csc4cnccc34)oc12
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(C3CCN(C(=O)CCc4ccccc4)CC3)c2)c2cc(-c3csc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-2-thieno[2,3-c]pyridin-3-yl-furo[2,3-c]pyridin-7-ylamine (20.8 mg, 0.05 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.05 mL, 6.5 mmol), dihydrocinnamic acid (0.06 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (13.5 mg, 0.07 mmol). The resulting solution was allowed to stir at room temperature overnight. The mixture was concentrated and then purified by MDP to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 9.50 (s, 1H), 9.10 (s, 1H), 8.59 (d, J=6.1 Hz, 1H), 8.72 (d, J=6.1 Hz, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.28 (s, 5H), 4.54 (m, 1H), 4.04 (m, 2H), 3.10 (m, 2H), 2.99 (m, 2H), 2.67 (m, 2H), 2.19 (m, 2H), 1.95 (m, 2H); MS (ESI): 549.64 [M+H]+; HPLC tR=0.86 min (HPLC: Analytical—2 min).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12](Br)[CH:13]=[CH2:14]>>[CH2:14]([C:7]1([OH:11])[CH2:8][CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6]1)[CH:13]=[CH2:12]
Reactant: O=C1CCCC2(C1)OCCO2
Reactant: C=CCBr
Product: C=CCC1(O)CCCC2(C1)OCCO2
Yield: 84 %

Procedure:
The title compound is prepared from 1,4-dioxa-spiro[4.5]decan-7-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: 84% of theory; Mass spectrum (ESI+): m/z=181 [M+H—H2O]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH:8]([CH3:11])[CH:9]=[O:10].[CH2:13](O)[C:14](=[CH2:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(O)C(=C)C>C1CCCCC1>[CH3:11][C:8]([CH:3]1[CH2:4][CH2:5][CH:6]([CH3:7])[C:2]1([CH3:1])[CH3:12])([CH2:15][C:14]([CH3:16])=[CH2:13])[CH:9]=[O:10]
Reactant: CC(C=O)C1CCC(C)C1(C)C
Reactant: C=C(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: C=C(C)CC(C)(C=O)C1CCC(C)C1(C)C

Procedure:
A 1 liter 3 neck flask equipped with a Dean-Stark trap, mechanical agitator, condenser, thermometer and nitrogen sweep was charged with the aldehyde from Example 28, 122.9 g at approximately 90% purity (0.66 mole), 230 g of methallyl alcohol (3.20 moles), 1.0 g of p-TSA, and 500 ml of cyclohexane. The contents were refluxed for 72 hours taking off a water-methallyl alcohol distillate (18 ml). The batch was cooled, washed with 250 ml of 10% sodium carbonate and 250 ml of brine. The mixture was dried, filtered, and concentrated in vacuo to afford 311 g of a mixture of acetal, and starting material. Distillation from 2 g of soda ash afforded 119 g of starting aldehyde. The pot residue 134.8 g contains the crude acetal (IR (Neat), 2980, 1660, 1470, 1150, 1100 cm-1) which was taken up in 200 ml of tetraglyme and 3 g of citric acid. Under nitrogen the flask was heated to 185° C. and 4 ml of methallyl alcohol were collected (approximately 2.5 hours). The flask was cooled and the contents were poured into 500 ml of 10% sodium carbonate and extracted with 2×200 ml of ether. The ether was washed with 200 ml of 10% sodium carbonate, 250 ml of water, and 250 ml of brine. The batch was dried, filtered, and concentrated to afford 124.7 g of crude product. Distillation afforded 58 g of purified product (40% yield). BP 2° C./0.3 mmHg; 1H-NMR (300 MHz), δ 0.64 (3H, s), 0.78 (3H, d, J=6.78 Hz), 0.91 (3H, s), 1.05 (3H, s), 1.60 (3H, s), 1.5-1.9 (6H, m), 2.3 (2H, AB quartet, JAB =13.8 Hz), 4.63 (1H, s), 4.81 (1H, s), 9.73 (1H, s); 13C-NMR (75 MHz), δ 13.50, 14.67, 16.73, 23.34, 24.23, 27.84, 28.88, 44.24, 45.95, 46.32, 53.13, 56.56, 115.46, 141.53, 207.14; IR (Neat), 2980, 2700, 1720, 1460, 900 cm-1 ; MS (m/e), 222 (M+), 207, 166, 123, 109, 95, 41 (Base);
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1.CC(C)=[O:21].O>[B-](F)(F)(F)F.[Ag+].CO>[OH:21][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: O=C(O)CCCCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 100) in 500 ml. of acetone and 325 ml. of water at 3°C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0°-3°C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66°C., λ max.MeOH = 223 mμ (7800); ν max (KBR) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm-1 (olefin group).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Sc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(Sc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To 5 ml of chloroform were added 0.57 ml of triethylamine and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine, to which 0.6 ml of a chloroform solution containing 0.33 g of thiophenol was slowly added dropwise, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(thiophenoxy)pyrimidine (the present compound (97)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16](Br)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Yield: 50.1 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate D) (4.3 g, 11.10 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.61 g, 12.21 mmol), palladium tetrakistriphenyphosphine(0.77 g, 0.67 mmol) and sodium carbonate(2.82 g, 26.65 mmol) were mixed with ethylene glycol dimethyl ether(100 ml) and water(50 ml). The reaction mixture was heated to reflux overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography using ethyl acetate/methanol (98/2) as mobile phase to give 2.65 g of 1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.99 (d, J=1.02 Hz, 2H), 2.25(m, 2H), 2.47 (m, 2H), 3.07 (d, J=1.12 Hz), 3.59 (s, 2H), 4.80 (m, 1H), 5.52 (s, 2H), 7.07 (d, J=0.67, 1H), 7.15 (m, 3H), 7.37 (m, 6H), 7.66 (d, J=8.51, 2H), 8.37 (s,1H); LC/MS (MH+=477).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12.[H-].[Na+].Br[CH2:29][CH2:30][OH:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([CH2:29][CH2:30][OH:31])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: OCCBr
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1CCO
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (0.0041 M) of 11b-(2-chlorophenyl)-10-nitro-2,3,5,11b-tetrahydooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 30 ml of dry N,N-dimethylformamide was treated with 0.34 g (0.008 M) of a 57% dispersion of sodium hydride in mineral oil with stirring under nitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added and the reaction was heated to 90° for 3 hr. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloromethane which was then washed with 50 ml of water, 25 ml of a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether, and recrystallized from a mixture of dichloromethane and methanol to give the product as pale yellow prisms, m.p. 185°-190°(dec.).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[S:12]([N:15]([C:24]1[C:29]([O:30][CH3:31])=[N:28][C:27](Cl)=[C:26]([Cl:33])[N:25]=1)COCC[Si](C)(C)C)(=[O:14])=[O:13]>O1CCCC1>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[S:12]([NH:15][C:24]1[C:29]([O:30][CH3:31])=[N:28][C:27]([N:2]([CH3:3])[CH3:1])=[C:26]([Cl:33])[N:25]=1)(=[O:13])=[O:14]
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: COc1nc(N(C)C)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 67 using dimethylamine (5 mL of a 2M solution in tetrahydrofuran) and 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.1 g). Yield 0.015g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: CCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (181 mg, 0.57 mmol) [Prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.87 mmol) in Dichloromethane (4.23 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (295 mg, 0.632 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (240 mg, 0.37 mmol, 64.8% yield) as a white foam: LCMS (ES) m/e 645, 647 (M, M+2)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](O)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(O)nc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21

Procedure:
A mixture containing 16 g of 1-ethyl-6-fluoro-7-hydroxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 160 ml of phosphoryl chloride was heated under reflux for 20 minutes with stirring. After evaporation of excess phosphoryl chloride under reduced pressure, the residue was triturated with ice-water and the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water, dried, and recrystallized from acetonitrile to give 14 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 265°-267° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[NH:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CC(=O)Nc2sccc2C(=N)NO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS (ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:11]([CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc[nH]1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cccn1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.5 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (0.45 g, 4.8 mmol) and 1-(2-bromoethoxy)benzene (1.1 g, 5.3 mmol) in DMF (20 mL) was added K2CO3 (3.3 g, 24 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.1 g (˜100%) of crude 1-(2-phenoxyethyl)-1H-pyrrole-2-carbaldehyde as a light yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[ClH:16]>CCOC(C)=O.CCCCCC>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CN(C)S(=O)(=O)Oc1ccc(CO)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Oc1ccc(CCl)cc1

Procedure:
To a solution of JRL01115 (725 mg, 3.135 mmol) in dichloromethane (10 mL) at ice/water temperature was added thionyl chloride (0.35 mL, 4.703 mmol). After stirring at room temperature for 1 h, the volatiles were removed from the reaction mixture and the oil resulted co-evaporated 3 times with chloroform (3×30 mL) to give to LWO02144 as a yellow oil (767 mg, 98%); Rf 0.52 (EtOAc/hexane, 1:1), c.f. 0.19 (JRL01115); 1H (400 MHz, CDCl3) 2.99 (6H, s, NMe2), 4.58 (2H, s), 7.28 (2H AA′BB′) and 7.42 (2H, AA′BB′); LRMS (FAB+) 403.0 [18, (M+H+NBA)+], 391.2 (21), 249.9 [100, (M+H)+], 214.0 [45, (M+H—Cl)+], 113.0 (17); HRMS (FAB+) 249.02239, C9H12ClNO3S requires 249.02264. LWO02144 was very pure and hence was used without further purification.