Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH2:44]([O:51][NH:52][C:25]([C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][C:21](=[O:23])[CH3:22])[C:10](=[O:24])[C:9]=2[CH:8]=1)=[O:26])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)O)cc1C2=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)NOCc3ccccc3)cc1C2=O
Temperature: -15 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4,5-diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid (6.14 g) in dry dimethylformamide (1.1 l) and nitrogen at -15° C. was added dropwise N-methylmorpholine (3.71 g) as a solution in dimethylformamide (20 ml) during 5 minutes. Stirring at -15° C. was continued for 40 minutes before the dropwise addition of isobutylchloroformate (2.51 g) as a solution in dimethylformamide (10 ml) over 10 minutes. The mixture was stirred at -15° C. for 45 minutes when a solution of O-benzylhydroxylamine hydrochloride (2.93 g) in dimethylformamide (20 ml) was added dropwise. Stirring was continued for 5 hours at -15° C. and the mixture was then allowed to warm to room temperature. After 16 hours at room temperature, the dark solution was concentrated in vacuo. The gummy residue was triturated with ethyl acetate to yield a bright yellow solid. This was triturated with tetrahydrofuran and the insoluble material then washed with 5% aqueous sodium bicarbonate solution. The insoluble yellow solid was washed with water and dried in vacuo yielding the title compound, m.p. 192°-194° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(=O)[NH2:2].N1C=CC=CC=1.O=S(Cl)Cl>>[C:1]([CH:4]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])#[N:2]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C#N)C1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1-Benzyl 4-ethyl 2-carbamoylpiperidine-1,4-dicarboxylate (2.4 g, 7.18 mmol) was dissolved in pyridine (50 mL, 618.21 mmol). The mixture was cooled on an ice bath and SOCl2 (3.14 mL, 43.07 mmol) was added dropwise and left overnight at room temperature. The reaction mixture was evaporated and partitioned between diluted HCl and DCM. The aqueous layer was extracted with DCM and the combined organic layer was washed with water, dried over Na2SO4 and evaporated. Crude 1-benzyl 4-ethyl 2-cyanopiperidine-1,4-dicarboxylate (2.25 g, 99%) was isolated. 1H NMR (400 MHz, dmso) δ 1.21 (t, 3H), 1.54-1.66 (m, 1H), 1.98-2.12 (m, 2H), 2.29-2.37 (m, 1H), 2.83-2.91 (m, 1H), 3.04-3.16 (m, 1H), 3.83-3.91 (m, 1H), 4.02-4.18 (m, 2H), 5.13 (s, 2H), 5.25-5.31 (m, 1H), 7.28-7.40 (m, 5H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH:14][C:15](=[O:27])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)([CH3:3])[CH3:2].[CH2:28]([O:30][CH2:31][CH2:32]Br)[CH3:29]>CN(C=O)C.[F-].[K+]>[CH:1]([C:4]1[C:9]([O:10][CH2:29][CH2:28][O:30][CH2:31][CH3:32])=[CH:8][CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH:14][C:15](=[O:27])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)([CH3:2])[CH3:3]
Reactant: CCOCCBr
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c1C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of N-(2,6-diisopropyl-3hydroxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide (180 mg, 0.61 mmol) in DMF (3 ml) were added 2-bromoethyl ethyl ether (2 ml) and potassium fluoride catalyst carried on alumina (40 wt %, 355 mg, 2.39 mmol) followed by stirring at 50° C. for 3 hours. After the catalyst was filtered off, the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 90 mg (yield 42%) of N-(2,6-diisopropyl-3-(2-ethoxyethyloxy)phenyl)-2-[4-(3-hydroxypropyl)piperazin-1-yl]acetamide as colorless powdery crystals.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:5]=1)(=O)[CH3:2].C([BH3-])#N.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:30]([S:27]([N:24]1[CH2:23][CH2:22][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]4[CH:5]=[C:4]([C@@H:1]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH3:2])[S:8][CH:7]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28])[CH3:31]
Reactant: C1CCNC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(C)=O)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc([C@H](C)N5CCCC5)c4)cc23)CC1

Procedure:
To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 19, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a light yellow foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: [H-].[Na+].C1COCC1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCCC3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
48 mg of sodium hydride was added to a THF solution of 0.2 ml of pyrrolidine, followed by stirring at room temperature for 1 hour. 54 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone was added, followed by reflux with heating for 10 hours. Water was added, the mixture was extracted with ethyl acetate, and the extract was purified by TLC (developing solvent, chloroform:methanol=9:1) to obtain 12 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: C[N:2]1CCOCC1.[CH:8](=[C:12]1[C:21]2[CH:20]=[C:19]([C:22]([OH:24])=O)[S:18][C:17]=2[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11].ClC(OCC(C)C)=O.N>CCOC(C)=O.O.C1COCC1>[CH:8](=[C:12]1[C:21]2[CH:20]=[C:19]([C:22]([NH2:2])=[O:24])[S:18][C:17]=2[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=C1CCCCc2sc(C(=O)O)cc21
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC=C1CCCCc2sc(C(N)=O)cc21
Reaction time: 0.03 h

Procedure:
N-Methylmorpholine (0.69 ml) was added to a mixture of 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxylic acid (1.05 g) and THF (10 ml) at −15˜−20° C. under nitrogen atmosphere, and isobutyl chloroformate (0.82 ml) was added thereto over 2 minutes. The mixture was stirred under the same condition for 30 minutes, and conc. ammonia (c.NH3) was added thereto. The mixture was stirred at r.t. for 2 hours. The reaction mixture was poured into a mixture of water and AcOEt to precipitate. The precipitate was collected by filtration, washed with water and Et20, and dried in vacuo to give 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (0.59 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>CN(C)C=O>[O:16]=[C:6]1[N:7]2[NH:8][CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[C:12]2=[C:3]([CH2:2][O:1][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[C:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1NCc1ccsc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2)N1CCOCC1
Temperature: 0 °C

Procedure:
2.62 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazin-7-one are dissolved in 80 ml of N,N-dimethylformamide and cooled to 3° in an ice-bath. 440 mg of 55 percent sodium hydride (NaH) dispersion are added portionwise thereto and the mixture is stirred for an additional hour after the last portion has been added. A solution of 1.5 g of N-chlorocarbonylmorpholine in 3 ml of N,N-dimethylformamide is now added dropwise thereto. The reaction mixture is left to stir at about 5° for an additional 45 minutes and poured into 800 ml of ice-water, whereby the crude product crystallizes out. After washing with water and drying, the crude product is purified by chromatography on silica gel and recrystallization. There is obtained (4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]-thieno[2,3-d]pyridazin-10-yl)methyl-4-morpholinecarboxylate of m.p. 207°-210° (acetonitrile).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: Clc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)c1cccc(CNc2cccn3nc(Cl)nc23)c1

Procedure:
160 b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-methanesulfonyl-benzylamine (450.0 mg, 2.429 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.429 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.97 (s, 1H), 7.93-7.87 (m, 2H), 7.68 (d, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.35 (d, J=7.8 Hz, 1H), 5.51-5.44 (m, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.07 (s, 3H). MS=337, 339 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:14])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Yield: 66.4 %

Procedure:
A solution of 4-[-2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.563 g) in warm methanol (5 mL) was treated with 1N sodium hydroxide (3.3 mL). Within 5 minutes water (30 mL) was added, then after the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (4.1 mL) and extracted with dichloromethane (1×60 mL, 2×10 mL). The combined organic layers were washed with water, then dried (MgSO4) and evaporated. The resulting yellow foam was taken up in diethyl ether, and after the the mixture was filtered to remove some insoluble material, the fillrate was evaporated and the residue was lyophilized from benzene to furnish 0.36 g of 4-[2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(S(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (735.3 mg, 1.421 mmol) in DCM (14.2 mL) at 0° C. was treated with triethylamine (0.594 mL, 4.26 mmol), followed by methanesulfonyl chloride (0.221 mL, 2.84 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A. The corresponding fractions were collected and concentrated under reduced pressure. The resulting residue was taken up in DCM and washed with saturated aqueous K2CO3 to generate the free base. The organic layer was separated, dried over Na2SO4, and filtered. Evaporation of the filtrate and lyophilization gave the title compound as an off-white solid (229.6 mg, 33.6%). 1H NMR (500 MHz, DMSO-d6) 1.18 (d, J=6.3 Hz, 6H), 1.88 (m, 2H), 2.07 (m, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.89 (m, 2H), 2.97 (s, 3H), 3.29 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.09 (m, 1H), 4.16 (s, 2H), 4.52 (tt, J=8.1, 3.9 Hz, 1H), 5.57 (d, J=8.3 Hz, 1H), 7.01 (m, 1H), 7.30 (m, 2H); ESI-MS m/z [M+H]+ 481.90.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[F:50])[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([NH:27][C:28]2[CH:29]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:47]=[CH:48][C:49]=2[F:50])=[O:15])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: O=C(O)c1ccn(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1ccn(Cc2ccccc2)c1
Yield: 24.3 %

Procedure:
Using 1-benzyl-1H-pyrrole-3-carboxylic acid (276 mg, 1.37 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (120 μL, 1.37 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.92 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (114 mg, 24%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.7 %

Procedure:
A solution of tert-butyl [(4-bromophenyl)amino]acetate (intermediate 1, 5.86 g, 20.5 mmol), methanesulfonyl chloride (2.58 g, 1.74 mL, 22.5 mmol), triethylamine (4.15 g, 5.71 mL, 41.0 mmol) and 4-dimethylaminopyridine (260 mg, 2.05 mmol) in dichloromethane (100 mL) was heated at reflux for 14 h. A second portion of methanesulfonyl chloride (2.58 g, 1.74 mmol, 22.5 mmol) was added and heating at reflux continued for a further 48 h. The reaction was cooled to room temperature and extracted with aqueous hydrochloric acid solution (1.0 M; 3×50 mL). The organic phase was dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound as a pale cream solid (2.37 g, 32%). LC/MS: 3.35 min; z/e 381 and 383, calcd (M+18) 381 and 383. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.35 (2H), 4.30 (2H), 3.10 (3H), 1.45 (9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C:13]([NH2:15])=O)=[CH:7]2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH:7]=[C:8]([C:13]#[N:15])[N:9]=1
Reactant: NC(=O)c1cc2cccc(F)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cccc(F)c2c(Cl)n1
Yield: 281.6 %

Procedure:
A solution of 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (5 g, 5.5 mmol) in POCl3 (46.23 g) was heated to reflux for 4 hours and was subsequently concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=5:1-2:1 gradient) to give the title compound (3.2 g, 35%). ESI-MS m/z [M+H]+ 207.1.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][OH:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][O:5][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(C)c(CO)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(COC(=O)CCC(=O)O)c(C)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A mixture of 1.50 g (0.01 mol) of 2,4,6-trimethylbenzyl alcohol, 1.00 g (0.01 mol) of succinic acid anhydride, 3.25 g (0.01 mol) of cesium carbonate, and 100 ml of dioxane was stirred at reflux temperature for 4 hours. The reaction mixture was cooled to room temperature and then filtered to remove the solid cesium carbonate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (acetone-hexane) to provide 1.167 g of succinic acid mono-(2,4,6-trimethylbenzyl) ester (46.62%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH:39]1[C:51]2[C:50](=[O:52])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1>>[OH:52][C:50]1([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:51]2[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=2[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C3(O)c4ccccc4-c4ccccc43)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(9-Hydroxyfluoren-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 9-fluorenone instead of benzophenone) as a colourless foam.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29]>CN(C=O)C>[Cl-:1].[CH2:28]([N+:30]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH3:29]
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[N+](CC)(CC)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccccc4)ccc3CC2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added triethylamine (180 μl). The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give triethyl[4—(7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl]ammonium chloride (Compound 25) (176 mg) as colorless crystals.