Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:19])[CH3:18]>>[C:17]([O:20][N:21]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:19])[CH3:18]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(=O)ONC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
Benzyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (50) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(benzyloxy) carbonyl]amino acetate according to Scheme 2. (0.33 g, 28%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.21-8.47 (2H, m), 7.79-7.88 (1H, m), 7.65-7.74 (1H, m), 7.30-7.41 (3H, m), 7.16-7.24 (2H, m), 5.18 (2H, br. s.), 3.31 (3H, s), 2.29 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:17]([CH2:18][CH3:19])[N:16]=[N:15][C:8]=2[C:9]([NH:13][NH2:14])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH3:20][C:21]([CH3:23])=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:17]([CH2:18][CH3:19])[N:16]=[N:15][C:8]=2[C:9]([NH:13][N:14]=[C:21]([CH3:23])[CH3:20])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(NN)c2nnn(CC)c12
Reactant: CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc(NN=C(C)C)c2nnn(CC)c12
Reaction time: 8 h
Yield: 95 %

Procedure:
2.6 g. of 1-ethyl-4-hydrazino-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester (0.01 mol.) are dissolved in 10 ml. of acetone. One drop of acetic acid is added and the mixture is allowed to stand overnight. The excess acetone is distilled off in vacuo and the residue is recrystallized from petroleum ether to obtain 1-ethyl-6-methyl-4-[2-(1-methylethylidene)hydrazino]-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester in 95% yield, m.p. 68°-72°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[N:10]=[C:11]([C:14]([NH2:16])=O)[S:12][CH:13]=1)(=[O:8])[CH3:7]>CN(C)C=O>[C:6]([C:9]1[N:10]=[C:11]([C:14]#[N:16])[S:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1csc(C(N)=O)n1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1csc(C#N)n1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Phosphorus oxychloride (8.5 ml) was added slowly to a solution of 4-acetyl-2-thiazolecarboxamide (10.0 g) in N,N-dimethylformamide (500 ml) at 0°-5° C. with cooling on an ice-water bath. The mixture was stirred at 0°-5° C. with cooling on an ice-water bath for 4 hours and then was poured into ice water (400 ml). The solution was extracted with ethyl acetate (750 ml×2). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from water to afford 4-acetyl-2-cyanothiazole (6.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[N+:22]([CH3:25])([O-:24])=[O:23].CN(C)C(N(C)C)=N>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:25][N+:22]([O-:24])=[O:23])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC[C@H](Nc2nc(Cl)ncc2F)C1

Procedure:
To a solution of (5)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate, 62a, (2.58 g, 8.22 mmol) in nitromethane (44.53 mL, 822.3 mmol) was added 1,1,3,3-tetramethylguanidine (1.55 mL, 12.33 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc) then a second chromatography (CH2Cl2:20% MeOH in CH2Cl2). Fractions containing pure product were combined and concentrated to give 1.8 g of 62b
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([B:29]1[O:37][CH:36]2[C:31]([CH3:41])([CH:32]3[CH2:38][CH:34]([CH2:35]2)[C:33]3([CH3:40])[CH3:39])[O:30]1)[CH2:13][C:14]1[C:15]([O:27][CH3:28])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[NH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CO>[C:48]([O:47][C:46]([NH:45][CH2:44][CH2:43][NH:42][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([NH:3][C@H:12]([B:29]1[O:37][CH:36]2[C:31]([CH3:41])([CH:32]3[CH2:38][CH:34]([CH2:35]2)[C:33]3([CH3:39])[CH3:40])[O:30]1)[CH2:13][C:14]1[C:15]([O:27][CH3:28])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:11])=[O:1])=[O:52])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1c(C[C@@H](B2OC3CC4CC(C4(C)C)C3(C)O2)N2C(=O)c3ccccc3C2=O)cccc1C(=O)OC(C)(C)C
Solvent: CO
Product: COc1c(C[C@H](NC(=O)c2ccccc2C(=O)NCCNC(=O)OC(C)(C)C)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C

Procedure:
To tert-butyl 3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from Step 1, Example 53) in 2 mL methanol was added tert-butyl 2-aminoethylcarbamate (1.1 eq). The resulting reaction mixture was stirred at reflux for 2 hr. Methanol was then removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2)[NH:10][C:9]1=O.O=P(Cl)(Cl)[Cl:24].C(N(C(C)C)CC)(C)C>>[Cl:24][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11]([N:10]=1)=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(=O)[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1

Procedure:
A mixture of Example 1A (15.9 g, 49.6 mmol) in POCl3 (55 ml, 590 mmol) and diisopropylethylamine (55 ml, 315 mmol) was heated at 90° C. for 1.5 hours. The reaction mixture was concentrated. The residue was treated with ice and saturated NaHCO3 carefully and then extracted with ethyl acetate. The insoluble material suspended in the two layers was filtered, washed with ether and water, and oven dried to provide the title compound. The two layers in the filtrate were separated. The aqueous layer was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated, and triturated (twice) with ethyl acetate/ether to provide additional title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:27](=[O:29])[CH3:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 3.58 g (12.1 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 100 ml of chloroform first 1.68 ml (12.1 mmol) of triethylamine, then under constant ice-cooling and stirring 1.15 ml (12.1 mmol) of acetic anhydride were added. Stirring was continued for additional 2 hours, then the solution was extracted with 3×100 ml of water, the organic layer was dried and evaporated under reduced pressure. The crystalline residue was recrystallized from 40 ml of isopropanol to obtain 3.50 g (85.7%) of the aimed product, m.p. 220°-222° C. After repeated recrystallization the m.p. increased to 223°-225° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH2:34][C:35](OC)=[O:36]>CN(C)C=O>[F:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: COC(=O)CF
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CF)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:22][C:15]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of N,N-diisopropylamine (3.6 mmol) in THF (9 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of n-BuLi (2.5M in hexanes, 3.3 mmol) was added dropwise over 3 minutes. After 30 minutes of stirring, a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.1 mmol) in THF (9 ml) was added dropwise over 9 minutes. After an additional 2 hours of stirring at −78° C., chlorotrimethylsilane (3.1 mmol) was added dropwise over 1 minute. After 1 hour of stirring at −78° C., the reaction was quenched with saturated NH4Cl(aq) (10 ml), warmed to room temperature, and partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc and the organic layers combined, washed with brine, dried (MgSO4), concentrated, and purified by silica gel chromatography (isocratic CHCl3) to give the title product as a white solid (82%). ESMS [M+H]+: 410.8.
Reaction SMILES: [CH:1]1([N:7]([CH2:21]CC2C=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][CH:30]([CH3:34])[CH2:31]CN.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][C:30]([CH3:34])([CH3:31])[CH3:29])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)CCN
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: CC(C)(C)CN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3,3-dimethyl-propylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH:17]=[CH:18][C:19](Cl)=[O:20]>ClCCl>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:20])/[CH:18]=[CH:17]/[C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: CNOC
Reactant: COc1cccc(C=CC(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(/C=C/C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].Cl>O1CCCC1.O>[S:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:11][S:12](=[O:15])(=[O:14])[NH2:13])(=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 63.1 %

Procedure:
A 57% oil dispersion of sodium hydride (11.8 g, 0.28 mole NaH) was added to 150 ml of tetrahydrofuran. The suspension was stirred and gently heated, and 15.84 g (0.12 mole) of 1,7-heptanediol in 75 ml of tetrahydrofuran was added gradually over a period of 90 minutes. An additional 25 ml of tetrahydrofuran was then added, and the reaction mixture was stirred at reflux for five hours. An additional 150 ml of tetrahydrofuran was added, and to the stirred warm mixture there was added dropwise a solution of 28.9 g (0.25 mole) of sulfamoyl chloride in 150 ml of tetrahydrofuran over a two hour period. The reaction mixture was stirred at reflux for five hours, then cooled and treaated dropwise with 125 ml of water. The mixture was acidified with 2N hydrochloric acid, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give a yellow solid which was recrystallized from an ethyl acetate--hexane mixture to give 22.0 g of 1,7-heptanediol disulfamate as colorless granules, m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][N:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].C(N(CC)CC)C>C(O)(C)C>[CH2:1]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[CH2:21][N:23]([CH2:24][CH2:25][N:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:22])=[CH:17][CH:18]=1)[S:9]([CH3:12])(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCn1ncc2ccccc2c1=O
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C2CO2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1

Procedure:
2-{4-(N-Benzylmethanesulphonamido)phenyl]oxirane (1.5 g), N-methyl-2-(phthalazin-1-on-2-yl)ethylamine (1.4 g) and triethylamine (1.4 g) in isopropanol (50 ml) were stirred at reflux temperature for 5 hours. The solvent was evaporated, the residue dissolved in methylene chloride and washed three times with sodium carbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). Combination and evaporation of the appropriate fractions gave a foam which was chromatographed a second time on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methyl isobutyl ketone (MIBK) containing acetone (0% up to 20%). The appropriate fractions were combined and evaporated then re-evaporated from diethyl ether to give the title compound as a foam, yield 450 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([CH2:30][NH2:31])[OH:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:31][CH2:30][CH2:28][OH:29])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCCO)nc3cc(Cl)ccc23)CC1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and ethanolamine (100 μL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1.CCN(C(C)C)C(C)C>C(O)(C)C>[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27]1
Reactant: NC1CCCOC1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4NC4CCCOC4)cc3)nc2c1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a microwave vial was charged with N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.25 g, 0.71 mmol), tetrahydro-2H-pyran-3-amine hydrochloride (0.19 g, 1.4 mmol), and DIPEA (0.49 mL, 2.8 mmol) in isopropyl alcohol (2 mL). The reaction was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 200° C. for 30 min (200 watts, Powermax™ feature on), then at the same temperature for another 15 min. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×) and the combined organics was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 420.0 (M+1). IC50 (uM) ++++.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH2:14]Cl.O>CN(C)C=O>[Cl:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:14][C:13]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:3]=1
Reactant: Oc1cc(Cl)sn1
Reactant: COc1ccc(OC)c(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c(COc2cc(Cl)sn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (4.0 g, 0.03 mole) in 15 ml of dimethyl formamide was added dropwise to a stirred suspension of 60% NaH in oil (1.4 g, 0.035 mole) in 25 ml of dimethyl formamide at 0° C. under N2. After 15 minutes, a solution of 2,5-dimethoxybenzyl chloride (5.6 g, 0.03 mole) in 10 ml of dimethyl formamide was added dropwise and the mixture was stirred at room temperature for 24 hours. The dark reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether extract was washed with water, dried (MgSO4), and concentrated. The residual white solid was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. 5-Chloro-3-(2,5-dimethoxybenzyloxy)isothiazole was obtained as a white solid; 4.7 g; mp 52°-55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Na].Cl.[C:15](#[N:17])[CH3:16]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:16][C:15]#[N:17])=[O:9])=[CH:11][CH:12]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3) δ:3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[CH3:2].[OH-:19].[K+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:17][C:16](=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCOc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).