Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:20]([CH2:32]Cl)=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][N:24]([C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH2:32][C:20]4=[N:19][C:14]=3[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Yield: 96.1 %

Procedure:
The method described in Part D of Example 365 was used to treat tert-butyl 2-[7-benzyloxy-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (23.55 g, 50.43 mmol) with potassium tert-butoxide (55.47 mL of a 1 M solution in THF) with the modification that crude product mixture was purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 66-minute gradient from 0:100 to 7:93) to provide 20.87 g of tert-butyl 3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate. Material from a different run was used in Part I.
Reaction SMILES: C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1.C(O)C.Cl[C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]([CH3:28])[N:18]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][C:19]1[N:18]=[C:17]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH3:29])[CH:31]=[CH:32]3)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CCOC(=O)c1cnc(C)nc1Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1-c1ccc2c(ccn2C)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
In a mixture of saturated NaHCO3:toluene:ethanol (1:2:1) (12 mL) was dissolved ethyl 4-chloro-2-methylpyrimidine-5-carboxylate (500 mg, 2.49 mmol), N-methylindole-5-boronic acid (872 mg, 4.98 mmol) and to this was added tetrakis(triphenylphosphine)-palladium(0) (58 mg). The reaction stirred at 75° C., under Ar, overnight. The reaction was allowed to cooled to RT, diluted with ethyl acetate (25 mL) and water (25 mL) and filtered free of insolubles. The organic phase was washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), evaporated at reduced pressure to give a reddish thick foam, and purified by chromatography (Biotage Si-25 column, 15-40% ethyl acetate/hexane) to give ethyl 2-methyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylate as a thick clear oil. The oil solidified overnight (391 mg, 53% yield). MS (ESI) m/z: 296.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][O:21][CH:22]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]([OH:25])=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Li]CCCC.[CH2:51]([C@@H:58]1[CH2:62][O:61][C:60](=[O:63])[NH:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:20][O:21][CH:22]([C:26]2[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]([N:59]2[C@H:58]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:62][O:61][C:60]2=[O:63])=[O:25])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of step (a) above (1.0 g, 1.7 mmol) was dissolved in anhydrous dichloromethane (50 ml). Dimethylformamide(0.05 ml) was added followed by oxalyl chloride (0.2 ml, 2.3 mmol) dropwise. After stirring at 25° C. for 0.5 hours the solvent was removed in vacuo. The resulting residue was azeotroped with toluene (2×50 ml) then, as a solution in anhydrous toluene (5 ml), added at -78° C. to the lithium anion of (4R)-4-benzyl-2-oxazolidinone (generated by adding n-BuLi (1.1 ml, 1.6M, 1.7 mmol) to a solution of (4R)-(+)-4-benzyl-2-oxazolidinone (0.301 g, 1.7 mmol) in tetrahydrofuran (5 ml) at -78° C.). The resulting colorless solution was stirred at -78° C. for a further 0.75 hours and quenched by addition of saturated ammonium chloride solution (30 ml). The product was extracted into ethyl acetate (2×30 ml) then the organic layer was dried over MgSO4 and filtered. The clear oil obtained after removal of solvent in vacuo was purified by chromatography on silica gel eluting first with 20% ethyl acetate/hexane to obtain the title compound, diastereomer A (0.350 g), and then with 30% ethyl acetate/hexane to obtain the title compound, diastereomer B (0.380 g). Diastereomer A was converted to a mixture (1:2) of diastereomer A and diastereomer B by treating a solution in dichloromethane with anhydrous triethylamine for 16 hours. The solvents were evaporated and the mixture separated by chromatography as described above to obtain diastereomer B: 1H NMR (250 MHz, CDCl3) δ 7.78 (s, 1H), 7.70 (s, 2H), 7.10-7.30 (m, 8H), 6.88 (m, 2H), 5.86 (s, 1H), 4.62 (m, 1H), 4.06-4.12 (m, 2H), 3.68 (m, 2H), 3.54 (d, J=7 Hz, 1 H), 3.22 (d, J=7 Hz, 1 H), 2.96 (m, 3H), 2.54 (dd, J=7, 2 Hz, 1H), 2.1 (m, 2H), 1.8 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:4]=[CH:3][CH2:2]1>[C].[Pd]>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:4]=[CH:3][CH2:2]1
Reactant: O=C(CN1C=CCOc2ccccc21)OCc1ccccc1
Agent: [Pd]
Product: O=C(O)CN1C=CCOc2ccccc21

Procedure:
Catalytic reduction of benzyl 1,5-benzoxazepine-5-acetate derivative obtained in Examples 27-35 is carried out using 10% palladium-carbon as a catalyst in a manner similar to that described in Example 17 to give 1,5-benzoxazepine-5-acetic acid derivative shown in Table 3.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)=[N:6]1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O.O>[NH:27]1[C:1]([CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]3[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[N:6]2)=[N:2][N:29]=[N:28]1
Reactant: N#CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCc1nnn[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
A mixture of 3-[2-(2-cyanoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.35 g), sodium azide (0.20 g) and triethylamine hydrochloride (0.21 g) in N-methylpyrrolidone (10 ml) was stirred at 150° C. for 4 hours under nitrogen atmosphere. The reaction mixture was poured into water (30 ml), acidified with 10% hydrochloric acid (5 ml), and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (20:1) as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 3-[2-{2-(1H-tetrazol-5-yl)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.06 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][C:4]1([CH3:19])[CH3:18]>CO.[Pd]>[CH3:1][N:2]([CH3:20])[CH:3]1[C:4]([CH3:19])([CH3:18])[CH2:5][NH:6][CH2:7]1
Reactant: CN(C)C1CN(C(=O)OCc2ccccc2)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CNCC1(C)C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution of racemic phenylmethyl 4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinecarboxylate (assumed 0.6565 g, 2.376 mmol) in MeOH was added 10% Pd/C (50% water, 195 mg). The mixture was hydrogenated under balloon pressure for 1 h, and then filtered. The solution was concentrated in vacuo to afford racemic N,N,4,4-tetramethyl-3-pyrrolidinamine (0.3479 g, quantitative yield) as an almost colorless oil. LCMS: (M+H)+: 143.1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:39])([F:38])[C:33]1[CH:37]=[CH:36][NH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:35]3[CH:36]=[CH:37][C:33]([C:32]([F:39])([F:38])[F:31])=[N:34]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(-n3ccc(C(F)(F)F)n3)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2.5 ml of absolute acetonitrile, and 656 mg (4.82 mmol) of 3-(trifluoromethyl)-1H-pyrazole, 157 mg (0.48 mmol) of caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg (0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 41 mg (33% of theor.) of the target compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(Br)ccc2s1

Procedure:
Starting from 2.99 g (14.7 mmol) of 5-bromo-2-fluorobenzaldehyde, by general method A with 0.88 g (22.1 mmol) of sodium hydride (60%) and 1.72 g (16.2 mmol) of methyl mercaptoacetate, 2.76 g (69.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Cl)=[CH:9][CH:8]=1.C(O)C>O>[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:8]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a 1 L volume four-necked flask, sodium methanesulfinate (31.3 g), 4-fluorophenacyl chloride (21-b) (48.1 g), and ethanol (300 ml) were added under a nitrogen atmosphere, and heated to reflux for 1 hour. After the mixture was cooled to room temperature, water (500 ml) was added. The precipitated solids were collected by filtration, washed with water, and dried. The solids were dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization (hexane—ethyl acetate) acetate) to give 51.9 g of 1-(4-fluorophenyl)-2-methylsulfonylethan-1-one (7-2-3).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29][CH2:37][CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: ClCCCN1CCOCC1
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(OCCCN4CCOCC4)cc3n2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10−5 mol) in DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10−4 mol) and the reaction mixture is heated to 80° C. N-(3-chloropropyl)morpholine (39 mg, 2.36.10−4 mol) is then added, and the mixture is stirred at 80° C. for 4 hours, cooled to room temperature and the solvent is evaporated. The resulting residue is purified by flash chromatography to afford the desired [2-(4-acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1-n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 2-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale pink solid (85 mg, 21%).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCC(CCC(OS([O-])(=O)=O)CC(C)C)CC.[Na+].[C:64](Cl)([Cl:66])=[O:65]>C(N(CC)CC)C>[CH2:1]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C:64]([Cl:66])=[O:65])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: O=C(Cl)Cl
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)Cl

Procedure:
For example, C12H25S(CH2CH2O)10H, such as Tergitol 12-M10, can be reacted with phosgene in the presence of triethyl amine to yield the corresponding acid chloride, C12H25S(CH2CH2O)10COCl, which in turn, is reacted with a fluoroaliphatic alcohol such as (CF3)2CFO--CF2CF2 --CH2CH2CONH(CH2)3OH, disclosed in U.S. Pat. No. 3,697,564, in the presence of triethylamine in diethyl ether to yield a product of the formula (CF3)2CFO--CF2CF2CH2CH2CONH(CH2)3OCO(OCH2CH2)10S--C12H25.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (228 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (373 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 577.0 (M+H)+.
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>O>[C:18]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1)(=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: C=C1CC(=O)O1
Solvent: O
Solvent: CCO
Product: CC(=O)CC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Yield: 95 %

Procedure:
The mother liquor obtained is re-used in four further reaction cycles by using it at 80° C. to replace fresh ethanol containing 50% by weight of water for dissolving 2.86 kg per hour of 5-amino-2-benzimidazolone at such a rate that 26.86 kg per hour of amine solution can be reacted as described above with 2.06 kg per hour of diketene. Workup gives 4.25 to 4.34 kg per hour of 5-acetoacetylamino-2-benzimidazolone of consistent quality, corresponding to a yield of 95 to 97% based on amine.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:5][CH:4]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[CH2:3]1.O1CCOCC1.[OH-].[Na+].CO>O.C(Cl)Cl.CCO>[CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:5][C@@H:4]([NH:29][S:30]([CH:33]2[CH2:34][CH2:35]2)(=[O:31])=[O:32])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C4CC(NS(=O)(=O)C5CC5)CC4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: C[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 10 %

Procedure:
A mixture of N-(3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (7.1 g, 13.9 mmol), 1,4-dioxane (139 mL) and aqueous 1 N NaOH (30.0 mL, 30.0 mmol) was heated at about 60° C. for about 2 h. The reaction was cooled to ambient temperature, diluted with water (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was triturated with EtOAc (50 mL) and filtered to give a tan solid, which was purified by chiral preparative HPLC (Table 3, Method 3, Rt=18 min, or =negative). The product containing fractions were combined and concentrated to give a pale yellow solid. The solid was dissolved in a 1:1 mixture of DCM:MeOH (about 100 mL), 10 g of silica gel was added, and the mixture was concentrated. The resulting mixture was purified by silica gel chromatography using a gradient of 0-100% DCM/MeOH/Et2NH (990:9:1) to DCM/MeOH/Et2NH (970:27:3). The product-containing fractions were combined and concentrated to give a white solid. The solid was dissolved in boiling EtOH (150 mL) and sonicated for about 1 h. The solvent was removed under reduced pressure and the solid was dried in a vacuum oven at about 70° C. for about 72 h. Water (12 mL) and EtOH (3 mL) were added, and the resulting slurry was refluxed for 2 h. The slurry was cooled to ambient temperature, followed by further cooling at about 0° C. in an ice bath. The solids were filtered while rinsing with ice-cooled water (about 3 mL) and dried in a vacuum oven to give N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.5 g, 10.4%) as a white solid with 0.5% EtOH: LC/MS (Table 2, Method a) Rt=1.61 min; MS m/z: 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([N-]C(C)C)(C)C.[Li+].[CH:24]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O1CCCC1>[CH:24]1([C:31](=[O:32])[CH:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: CCOC(=O)Cc1c(F)cc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of ethyl 2,4,6-trifluorophenylacetate (436 mg, 2.0 mmol) in 3 mL of tetrahydrofuran is cooled to −78° C., and lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 1.0 mL, 2.0 mmol) is added dropwise with stirring. The mixture is stirred at −78° C. for 1 h, and cycloheptanecarboxylic acid chloride (321 mg, 2.0 mmol) is added dropwise. The mixture is warmed to room temperature and acidified with 2 mL of 1.0 N hydrochloric acid. The product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 10% ethyl acetate in hexanes. Concentration provides ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate as a colorless oil (410 mg). MS: m/z 341.2 (M−H).