Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.68 g. (0.025 mole) of m-trifluoromethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oily residue of 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea HCl, m.p. = 164°-165° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2C(=O)O[C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]2)=[CH:11][CH:10]=1.C(#N)C.Br/[C:29](=[CH:35]\[C:36]([F:39])([F:38])[F:37])/[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([C:21]([F:22])([F:23])[F:24])=[C:35]([C:36]([F:39])([F:38])[F:37])[C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C(Br)=C/C(F)(F)F
Reactant: O=C1OC(C(F)(F)F)=NC1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
Triethylamine (1.1 g, 0.011 mol) is added dropwise to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.64 g, 0.01 mol) and acetonitrile (25 mL). After stirring for 10 minutes at room temperature, a solution of ethyl 2-bromo-4,4,4-trifluorocrotonate (2.47 g, 0.01 mol) and acetonitrile (1 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 2 hours then poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an orange oil which solidifies upon standing. Trituration with hexanes gives the title product as a yellow solid (2.36 g, 61.3%, mp 138°-140° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][O:52][C:53]1[N:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[CH:58][CH:57]=[C:56]2[NH2:63]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:19])[NH:63][C:56]2[C:55]3[C:60](=[CH:61][CH:62]=[C:53]([O:52][CH3:51])[N:54]=3)[N:59]=[CH:58][CH:57]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2nccc(N)c2n1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 118.9 %

Procedure:
A solution of acid (d) (7.9 g, 30 mmol) and triethylamine (4.2 ml, 3.03 g, 30 mmol) in N,N-dimethylformamide (50 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU) (9.5 g, 25 mmol). After 0.25 hours, amine (c) (3.5 g, 20 mmol) was added and the mixture heated at 50° C. overnight. Evaporation afforded an oil which was partitioned between ethyl acetate and dilute brine. Drying and evaporation afforded an oil (10 g) which was chromatographed on silica eluting with a 0–5% methanol in ethyl acetate gradient, affording an oil (6.0 g, 80%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C:9]1[N:14]=[C:13]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1cccc(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
A solution of acetic acid 6-tert-butoxycarbonylamino-pyridin-2-ylmethyl ester (0.85 g, 3.18 mmol) in dichloromethane (30.00 ml) was cooled to 0° C. and trifluoroacetic acid (2.40 ml) was added dropwise. After stirring at room temperature for 3 h, further trifluoroacetic acid (1.50 ml) was added and stirring was maintained for further 2 h. The reaction mixture was basified with 1 N sodium bicarbonate (54.00 ml) to a pH 8. The organic phase was separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated to yield pure acetic acid 6-amino-pyridin-2-ylmethyl ester (0.54 g, 100%) as a white solid, MS (ISP): m/e=167.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F-:13].[K+]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([F:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: [F-]
Agent: [K+]
Product: O=C(F)c1cc(F)c(F)cc1Cl

Procedure:
Into a 200 cc glass reactor equipped with a reflux condensor, 50 g of 2-chloro-4,5-difluorobenzoylchloride, 13.7 g of spray dried potassium fluoride and 100 g of sulforane were charged and reacted at 135° C. for 4 hours under stirring. After cooling, the inorganic salts were filtered off, and the residue was subjected to distillation under reduced pressure to obtain 42 g of 2-chloro-4,5-difluorobenzoyl fluoride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl fluoride were as follows.
Reaction SMILES: C([O:4][C:5]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH:9]([OH:23])[CH2:10][N:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C=C.O.C(N(CC)CC)C>C(O)C.[Cl-].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.[Rh+3].[Cl-].[Cl-]>[CH2:12]([N:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH:9]([OH:23])[CH2:8][O:7][C:6]1[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:5]=1[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCOc1c(OCC(O)CN(Cc2ccccc2)C(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Rh+3]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc([N+](=O)[O-])c1O

Procedure:
A solution of 19.4 g of 1-(2-allyloxy-3-nitro-phenoxy)-3-(N-benzyl-tert.-butylamino)-2-propanol in a mixture of 350 ml of ethanol, 35 ml of water and 5 ml of triethylamine, with the addition of 1 g of rhodium tris-(triphenylphosphine)chloride, is stirred under reflux for 45 minutes. After filtering and evaporating the filtrate, crude 1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanol is obtained in the form of a dark red oil, which is used further without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(OCC)C.CCCCCC>[C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[O:19][C:25](=[O:26])[NH:24][S:21]([Cl:20])(=[O:23])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2,6-diphenyl phenol (25.0 g, 101 mmol) in 250 mL ethyl ether was added dropwise to a solution of chlorosulfonyl isocyanate (9.7 mL, 112 μmol) in 100 mL hexane at -15° C. under an atmosphere of nitrogen. The resulting white suspension was allowed to warm to room temperature over 2 hours. Concentrated in vacuo and triturated with ice cold hexane. Vacuum filtration afforded the title compound as a white solid, mp 159°-162° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].[Br:6][C:7]1[O:11][C:10]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17]Br)[N:16]=2)=[CH:9][CH:8]=1.[C:20]([O-])(=[O:22])C.[Na+]>O>[Br:6][C:7]1[O:11][C:10]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17][C:20]([O:4][CH3:3])=[O:22])[N:16]=2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Reactant: Cc1oc(-c2ccc(Br)o2)nc1CBr
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(Br)o2)oc1C
Yield: 83 %

Procedure:
The N,N-dimethylformamide (1.5 mL) solution of 2-(5-bromofuran-2-yl)-4-(bromomethyl)-5-methyloxazole (32 mg, 0.1 mmol) and sodium acetate (12 g, 0.15 mmol) was stirred at 80° C. overnight. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain methyl {2-(5-bromofuran-2-yl)-5-methyloxazol-4-yl}acetate as a yellow oil (25 mg, 83%).
Reaction SMILES: [OH:1][C:2]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([O:38][Si](C(C)(C)C)(C)C)[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30](=[O:37])[NH:31]3)[CH3:13])[CH2:8][CH2:7]1)=[O:4].F.F.F.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[OH:1][C:2]([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([OH:38])[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30](=[O:37])[NH:31]3)[CH3:13])[CH2:8][CH2:7]1)=[O:4]
Reactant: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCCCCCCCCNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-[(9-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}nonyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 7; 0.8 g, 0.13 mmol) in tetrahydrofuran (5.1 mL) was added triethylamine trihydrofluoride (0.14 mL, 0.89 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 hours. The crude reaction was diluted with methylene chloride and the organic layer washed with sodium bicarbonate and brine, dried, filtered and evaporated. The crude product was purified by preparative reversed-phase HPLC (System 1) obtaining the title compound as a colourless solid (61%).
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6].N.[BH3-]C#[N:26].[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[NH2:26][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(=O)c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reaction time: 1.33 h
Yield: 93.4 %

Procedure:
A 25 mL microwave reaction vessel equipped with a stir bar was charged with 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-oxo-2-phenyl-ethyl)-amide (80 mg) and ammonia (1.5 mL, 7 M in methanol). A drop of acetic acid and NaCNBH3 (20 mg) were added to the reaction mixture and subjected to microwave at 80° C. for 80 min. The residue was taken up in ethyl acetate (30 mL) and saturated NaHCO3 (aq.) (30 mL). The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with sat NaHCO3 (3×10 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a solid (75 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a solution of methyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]propanoate (0.755 g, 1.64 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (0.736 g, quant.) as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH3+:51])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:52](O)(=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:51][C:52](=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@@H]([NH3+])Cc2cc(F)cc(F)c2)COC(=O)[C@@H]2CCCN2C1=O
Reactant: CCCC/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC/C=C/C(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)N[C@H]1COC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.89 g (2.75 mmol) of the compound from example 13A and 458.8 mg (3.58 mmol) of trans-2-heptenoic acid are introduced into dichloromethane (20 ml), cooled to 0° C., then treated with 2.09 g (5.51 mmol) of HATU and 462.7 mg (3.58 mmol) of ethyldiisopropylamine. The solution is stirred at 0° C. for 30 min, then a further 925.3 mg (7.16 mmol) of ethyldiisopropylamine are added, and it is stirred at room temperature for 18 h. The reaction solution is evaporated, and the residue is taken up using ethyl acetate and washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel using ethyl acetate/cyclohexane 1/2. 1.51 g (56% of th.) of the product are obtained.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:14]([OH:16])=[O:15].C([Li])(C)(C)C.[F:22]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.CCCCC>[F:22][C:3]1[C:4]2[CH2:5][O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][C:2]=1[C:14]([OH:16])=[O:15]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(O)c1sc2c(c1F)COc1ccccc1-2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 4H-thieno[3,2-c]chromene-2-carboxylic acid (1.65 g, 7.10 mmol) in THF (70 mL) at −78° C. was added a 1.5 M solution of tert-butyllithium in pentane (15 mL). The resulting solution stirred 1 hr at −78° C. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (7.2 g, 23 mmol) was added and the reaction warmed to room temperature over 2 hr. The reaction was quenched by the addition of 1 M HCl to effect pH 3. The aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to yield 3-fluoro-4H-thieno[3,2-c]chromene-2-carboxylic acid, which contained less than 40% 4H-thieno[3,2-c]chromene-2-carboxylic acid, which was utilized in the next step without purification (1.0 g). MS (Q1) 249 (M)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13]>>[CH3:1][S:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][C:16]2=[O:17]
Reactant: CSc1ccc(N)cc1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1cc(=O)c2cc(SC)ccc2[nH]1
Yield: 28.5 %

Procedure:
Using the method described in Example 18a with 4-methylthioaniline (20 g) and dimethyl-acetylene dicarboxylate (20.21 g) as reagents gave methyl 6-methylthio-4-oxo-1,4-dihydroquinoline-2-carboxylate (10.12 g), m.p. 264°-266° C. δ (360 MHz, DMSO-d6), 2.55 (3H, s, CH3S), 3.96 (3H, s, CH3O), 6.68 (1H, s, 3-H), 7.64 (1H, dd, 7-H), 7.83 (1H, d, 5-H) and 7.89 (1H, d, 8-H).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[NH:22][C:21]=2[CH:28]=1.[CH:29]1([CH2:32][NH:33][C:34](=[O:51])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[NH:42][C:43]2[C:48]([Cl:49])=[CH:47][N:46]=[C:45](Cl)[N:44]=2)[CH2:31][CH2:30]1.C(O)(C)C>C(#N)C.O>[Cl:49][C:48]1[C:43]([NH:42][C:36]2[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([NH:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[O:51])=[N:44][C:45]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[NH:22][C:21]=3[CH:28]=2)=[N:46][CH:47]=1
Reactant: O=C(NCC1CC1)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Solvent: O
Solvent: CC(C)O
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NCC4CC4)n3)cc2N1

Procedure:
10-Camphorsulfonic acid (21 mg, 0.090 mmol), 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (53 mg, 0.30 mmol) and N-Cyclopropylmethyl-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide (110 mg, 0.30 mmol) in Acetonitrile (3 mL) was irradiated in a CEM microwave (120° C., 40 min) Only partial conversion, due to poor solvation. Add Isopropyl alcohol (2 mL) and irradiate an additional 3 h, 120° C. Work up by pouring into 20 mL 1:1 water:satd. aq. sodium bicarbonate and extract with DCM (2×15 mL), wash with brine, dry over sodium sulfate and conc. onto 1 g silica gel. Chromatography (ISCO, 2×12 g silica, 0-5% MeOH:DCM) to afford 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-cyclopropylmethyl-3-fluoro-benzamide as an off white film (60 mg, 40%). LCMS: 495 (M+H); 1H-NMR (DMSO): 9.32 (s, 1H), 9.25 (s, 1H), 9.13 (s, 1H), 8.49 (m, 1H), 8.16 (s, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 7.19 (d, 1H, J=8.4 Hz), 7.09 (s, 1H), 6.92 (d, 1H, J=8.2 Hz), 3.31 (s, 2H), 3.07 (t, 2H, J=6.0 Hz), 2.55 (m, 2H), 2.03 (m, 4H), 0.89 (m, 1H), 0.35 (m, 2H), 0.14 (m, 2H); 19F-NMR (DMSO): −115.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH2:19]([I:22])[CH:20]=[CH2:21]>C1COCC1>[I-:22].[CH2:19]([N+:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1)[CH:20]=[CH2:21]
Reactant: C=CCI
Reactant: COc1ccc2nc(N3CCN(C)CC3)oc2c1
Solvent: C1CCOC1
Product: C=CC[N+]1(C)CCN(c2nc3ccc(OC)cc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 50 mg portion of 2-(4-methyl-1-piperazinyl)-6-methoxybenzoxazole was dissolved in 5 ml of THF. Under cooling with ice, 0.03 ml of allyl iodide was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature followed by reflux for 16 hours under heating. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate, extracted twice with 100 ml of water and then lyophilized to obtain 73 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.B(F)(F)F.CCOCC>CCOCC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: C1=COCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncn(C3CCCCO3)c2-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole) dihydropyran, 250 ml ethyl acetate and 4.0 g BF3.Et2O was refluxed for five days. The nearly clear solution was diluted with ether and filtered to remove 0.6 g insoluble starting material. The ether filtrate was washed several times with 10% NaHCO3 then dried and evaporated. TLC showed starting material still present, so the crude product was chromatographed on 2 lb. SilicAR CC-7, eluting with toluene containing 20 to 40% ethyl acetate. The pure 4,5-diphenyl-1-(2-tetrahydropyranyl) imidazole thus obtained weighed 30.3 g (82%) and had mp 170°-171°.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>CCCCC>[CH3:1][C:2]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH3:3]
Reactant: CC(C)(C)OO
Reactant: CC(C)=CC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC(C)(C)OOC(C)(C)CC(=O)CC(C)(C)OOC(C)(C)C
Temperature: 10 °C

Procedure:
A mixture of 6.9 g. (0.05 mole) of phorone and 23.2 g. (0.2 mole) of anhydrous 81% t-butyl hydroperoxide was diluted with 50 ml of pentane and the mixture stirred at 10° C., while 5.7 g. of 77% sulfuric acid solution was slowly added over a thirty minute time period. The mixture was then allowed to warm slowly to 25° C. and stirred for 72 hours. After the reaction mixture was washed with water and sodium bisulfite solution, it was dried over anhydrous magnesium sulfate, the drying agent separated and the pentane removed under reduced pressure. The product weighed 11.4 g. (71.7% of the calculated amount). The infrared spectrum showed a strong absorption in the 880 cm-1 region, usually associated with t-butylperoxy groups and no absorption in the regions ascribed to hydroxyl or olefin. A GLC scan showed one large major peak for the expected product. By active oxygen assay, the purity of the product was estimated at 93%.