Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:26]C(OC(C)(C)C)=O)[C:11]([O:13][CH2:14][C@H:15]([O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(#N)C>O>[NH2:26][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][CH2:14][C@H:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:16])=[O:12]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The solution of (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate 6 from Step 3 was added to a 570 L glass-lined reactor and rinsed with methyl tert-butyl ether (MTBE) (312.4 kg, 13.9 kg). The contents were concentrated under vacuum at a maximum W/G temperature of 40° C. until distillation stopped. Acetonitrile (CH3CN) (116 kg, 3.0 parts) was charged to the reactor and the vacuum distillation repeated until distillation ended. Additional acetonitrile (CH3CN) (112 kg, 2.9 parts) was charged to the reactor and the temperature was adjusted to 40° C. (39-41° C.). Methanesulfonic acid (MeSO3H) (6.97 kg, 0.18 parts) was charged to the reactor while maintaining the temperature at 40° C. (35-45° C.). The pump and lines were rinsed forward with acetonitrile (CH3CN) (3.9 kg, 0.1 part). The reaction was complete after two hrs (2-6 hrs expected) at 40° C. (35-45° C.) as determined by high pressure liquid chromatography (HPLC). The temperature of the mixture was adjusted to 22° C. (19-25° C.) and agitated for 32 hrs. The crude product was collected by centrifugation, the reactor, lines, and filter cake rinsed forward with acetonitrile (CH3CN) (38.7 kg, 1 part) and spun as dry as possible to provide a wet filter cake (10.9 kg). A portion of the wet filter cake (8.0 kg) was transferred to a 570 L glass-lined reactor. Acetonitrile (CH3CN) (278 kg, 10 parts) was charged to the reactor, the contents agitated, and the temperature adjusted to reflux (80-82° C.). Water (2.8 kg, 0.1 parts) was charged to the reactor, maintaining the temperature at 80-82° C. The suspension became a clear solution. The mixture was agitated at 80-82° C. for ca. 30 minutes. The solution was then cooled over 6 hrs to 22° C. (19-25° C.) with a slurry forming at 60° C. The slurry was held at 22° C. (19-25° C.) for an additional 2 hrs. The product, (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1, was collected by centrifugation and the reactor, lines, and filter cake were rinsed with 3 portions of methyl tert-butyl ether (MTBE) (30 kg each) and spun dry. The product was dried at a maximum temperature of 55° C. until LOD was ≦0.5% and acetonitrile is ≦400 ppm as determined by gas chromatography (GC) to provide 5.4 kg of (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(OCCN3CCOCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-morpholin-4-yl-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 354(MH+).
Reaction SMILES: [O:1]1[C:13]([CH3:15])([CH3:14])[C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8]C(=O)C.[CH2:17]([O:19][C:20](=[O:30])[C:21]([CH2:28][CH3:29])(CC)P(O)(O)=O)[CH3:18].[Na]>C(O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[C:28]([CH3:29])[CH2:8][CH2:7][CH:6]=[C:5]([CH3:12])[CH2:4][CH2:3][C:2]1([CH3:16])[O:1][C:13]1([CH3:15])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C=C(C)CCC=C(C)CCC1(C)OC1(C)C
Reaction time: 14 h

Procedure:
To a solution of 25 g. of 9,10-epoxy-6,9,10-trimethyl-undec-5-en2-one and 24.8 g. of diethyl phosphonoacetic acid ethyl ester in 160 ml. of absolute ethanol, there was added dropwise while cooling with ice, a solution containing 2.56 g. of sodium in 65 ml. of absolute ethyl alcohol. The mixture was allowed to stand for 14 hours at room temperature and evaporated subsequently under vacuum. The residue was poured into a saturated aqueous sodium chloride solution, exhaustively extracted with diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Fractional distillation at high vacuum gave 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadienoic acid ethyl ester. B.p. 110°-113°C./0.01 mm Hg; nD20 = 1.4792.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[F:1][C:2]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)nc1F
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 20 g. of 2,6-difluoropyridine in 100 ml. of concentrated sulfuric acid at about 20° C., was added 75 ml. of 90% fuming nitric acid over 20 minutes. The mixture was kept at room temperature overnight, warmed to 35° C. over 15 minutes and held at this temperature for 10 minutes. The solution was cooled and poured into ice. The oil was extracted with 400 ml. of ether and the ether extract was washed with bicarbonate solution until all of the acid was neutralized. The ether was dried, evaporated and the residue was distilled at 0.1 mm. The only fraction came over at 50° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.ClCCl>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 140 °C
Yield: 14 %

Procedure:
A degassed mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (45.8 mg, 0.207 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (8.1 mg, 9.87 umol, 5.0 mol %) in acetonitrile (0.74 mL) and 1M aqueous potassium carbonate solution (0.74 mL) was heated under microwave irradiation (140° C.) for 30 minutes. Further portions of the boronate ester (1.0 eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and 1M aqueous potassium carbonate solution (0.74 mL) were added and the mixture heated under microwave irradiation (140° C.) for an additional 30 minutes. The mixture was concentrated in vacuo and the residue dissolved in water and DMF, and acidified with 10% (v/v) sulfuric acid. The resultant solid was removed by filtration and the filtrate concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by preparative HPLC [0-30% MeCN/water modified with 0.1% formic acid] to afford an orange fluffy solid (5.1 mg, 14%). LCMS (Method E): RT=5.45 min, M+H+=436.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.NC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC(=O)O
Agent: CCCCCCC(=O)O
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 87 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 11.0 kg of aniline. The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with a 2N sodium hydroxide solution and subsequently with water until neutral. After removal of the solvent by evaporation, the resulting solid is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 87% and with a chemical purity exceeding 99%.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6]/[C:7](=[C:14]2\[C:15](=[O:26])[NH:16][C:17]3[C:22]\2=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=3)/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6]/[C:7](=[C:14]2\[C:15](=[O:26])[NH:16][C:17]3[C:22]\2=[CH:21][CH:20]=[C:19]([C:23](=[O:24])[NH2:29])[CH:18]=3)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:27][CH:28]=1
Reactant: N
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(Br)cc1)c1ccccc1
Product: NC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and ammonia Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C22H16BrN2O3
Reaction SMILES: [N+]12([O-])CCC(CC1)CC2.CN(CCN(C)C)C.C([Li])CCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](C=O)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.CCCCCCC.C(O)(C)C>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccnc2ccccc12
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Agent: [O-][N+]12CCC(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Solvent: CC(C)O
Product: c1ccc2ncccc2c1

Procedure:
The synthesis is carried out in a similar manner to Example A5 using 3.58 g (28.2 mmol) of azabicyclo[2.2.2]octane N-oxide, 4.70 ml (31.1 mmol) of TMEDA, 20.00 ml (32.0 mmol) of n-butyllithium (1.6 M in n-hexane) and 5.00 g (31.7 mmol) of quinoline-4-carbaldehyde. The 1H NMR spectrum of the crude product shows that the two diastereomers are formed in a 1:1 ratio. Chromatographic purification on a silica gel column (ethyl acetate/triethylamine, 9:1) provides 2.95 g (39%) of rubanol as a colourless solid. Semipreparative HPLC (Chiracel OD-H®, n-heptane/isopropanol 98:2, 0.5 ml/min, tr[(−)-rubanol]=52.1 min, tr[(+)-rubanol]=63.8 min) separates the erythro-enantiomers from each other to 99% ee in each case. 1H NMR (CDCl3, 400 MHz): 8.90 (d, 1H, 3J=4.6 Hz), 8.12 (dd, 1H, 3J=8.6 Hz, 4J=0.8 Hz), 7.97 (d, 1H, 3J=8.4 Hz), 7.69-7.64 (m, 2H), 7.43 (dt, 1H, 3J=7.0 Hz, 4J=1.2 Hz), 5.78 (d, 1H, 3J=3.5 Hz), 4.70 (br, 1H), 3.57-3.52 (m, 1H), 3.14-2.49 (m, 4H), 1.89-1.27 (m, 7H). 13C NMR (CDCl3, 101 MHz): 150.6 (q), 148.7 (t), 148.4 (q), 130.8 (t), 129.4 (t), 126.9 (t), 126.1 (t), 125.5 (q), 123.4 (t), 118.7 (t), 72.0 (t), 60.4 (t), 51.1 (s), 44.3 (s), 26.7 (s), 26.3 (s), 25.9 (s), 22.3 (t). Melting point: 222-224° C. [α]D20: +99° (c=0.51, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1[C:8]#[N:9].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1[C:8]1[NH:21][N:20]=[N:19][N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)oc2c(c1=O)CSc1ccccc1-2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)oc2c(c1=O)CSc1ccccc1-2
Temperature: 110 °C
Yield: 68.1 %

Procedure:
A mixture of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carbonitrile (3.14 g, 12.3 mmoles, described in Example 6), sodium azide (0.884 g, 13.6 mmoles) and ammonium chloride (0.130 g, 2.4 mmoles) in dimethylformamide (18 ml) is heated at 110° C. for 18 hr. The dark solution is evaporated and the residue is dissolved in water (50 ml). The aqueous solution is washed with ethyl acetate and acidified with 10% hydrochloric acid. The precipitate is collected, washed with water and crystallized from acetone-water to give the title compound (2.5 g), mp 247°-248° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][NH2:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[SH:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45]>C1COCC1.CC(=O)OCC>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][NH:9][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[N:50][C:42]=1[SH:41]
Reactant: NCC1CC2CCC1C2
Reactant: O=C(O)c1cccnc1S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCC1CC2CCC1C2)c1cccnc1S
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.5 %

Procedure:
5.0 g (40.0 mmol) of bicyclo[2.2.1]heptan-2-ylmethanamine, 16.0 g (42.0 mmol) of HATU and 5.8 ml (42.0 mmol) of NEt3 were added in succession to a solution of 6.2 g (40.0 mmol) of 2-mercapto-nicotinic acid in THF (320 ml), and the mixture was stirred for 4 d at RT. Dilution with EA was then carried out. The organic phase was separated off, washed with a 1M aq. Na2CO3 sol. and a 4M aq. NH4Cl sol., dried over MgSO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3→1:1→3:7) was carried out with the residue. The resulting prepurified product was dissolved in 1N aq. NaOH (100 ml) and the solution was washed with ether. The aqueous phase was adjusted to pH ˜2 with 2M hydrochloric acid. The resulting precipitate was filtered off and then washed with pentane and dried in vacuo. 5.3 g (20.2 mmol, 50%) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.C(OCC)C.CO>[ClH:23].[NH:8]1[CH2:11][CH:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][N:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2n[nH]c(-c3ccccn3)n2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(-c2nc(C3CNC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(5-pyridin-2-yl-1H-[1,2,4]triazol-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (3.13 g, 10.39 mmol) was suspended in a solution of HCl in dioxane (4M, 80 mL) and stirred at rt overnight. The reaction mixture was diluted with diethyl ether, filtered and the residue suspended in acetonitrile and stirred for 45 min at rt. The solid (hydroscopic) was isolated by filtration, partially dissolved in warm methanol and addition of diethyl ether resulted in precipitation of a yellow sticky solid which could not be filtered. The mixture was concentrated in vacuo and dried in a vacuum oven (40° C.) to obtain the desired compound as a light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:17])=[N:14][CH:15]=3)[N:10]([CH3:18])[N:9]=2)=[CH:4][C:3]=1[F:19].C(=O)=O.CC(C)=O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CCOC(C)=O>[NH2:17][C:13]1[N:12]=[C:11]2[N:10]([CH3:18])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[C:3]([F:19])[CH:4]=3)[C:16]2=[CH:15][N:14]=1
Reactant: Cn1nc(-c2ccc(N)c(F)c2)c2cnc(N)nc21
Reactant: CS(=O)(=O)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccc(NS(C)(=O)=O)c(F)c2)c2cnc(N)nc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 58) (0.13 g, 0.50 mmol) is dissolved in pyridine (1.5 ml) under an inert atmosphere of argon. The reaction mixture is cooled to −10° C. (dry ice/acetone bath) then methanesulfonyl chloride (0.078 ml, 0.75 mmol) is added drop wise over a period of 15 minutes. The reaction mixture is stirred at −10° C. for 30 minutes then allowed to warm to room temperature and stirred for further 3 hours. The reaction mixture is diluted with EtOAc (100 ml) and washed with water (3×40 ml) and brine (10 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with hot EtOAc (plus few drops of MeOH), filtered and dried under vacuum at 50° C. for 3 hours to afford the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:20][C:21]([F:39])([F:38])[C:22]1[N:27]=[C:26]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:29]([NH:28][C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:38])([F:20])[F:39])[N:27]=4)=[O:30])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Reactant: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Yield: 7.1 %

Procedure:
A solution of [4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol (170.0 mg, 0.67 mmol), phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate (281.9 mg, 1.00 mmol), and triethylamine (0.46 mL, 1.33 mmol) in DMF (5 mL) was stirred at rt for 3 d. The crude reaction mixture was purified directly by HPLC using a gradient of 20-90% MeCN in water to yield 21.1 mg (7%) of the title compound. 1H-NMR (DMSO-d6) 9.89 (bs, 1H), 9.72 (bs, 1H), 8.05-7.98 (m, 2H), 7.89 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.51-7.49 (m, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.64 (s, 1H), 5.19 (t, J=5.7 Hz, 1H), 4.74 (d, J=5.6 Hz, 3H); MS [M+H]+=444.1; LCMS RT=2.63 min.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CN(C)c1ccc(CBr)cc1
Product: CN(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
Similarly, N-cyclopropyl-N-[1-(4-dimethylaminobenzyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide and 1-bromomethyl-4-dimethylaminobenzene.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[C:14]1[C:13]([CH:12]=[O:19])=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:2]
Reactant: O=Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=Cc1ccccc1-c1c(O)cccc1O

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of ethanol were added 530 g. of benzaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated under reflux for 90 minutes with stirring and, after completion of the reaction, the reaction mixture was poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:11][C:7]1[C:6]([F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[F:10]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1c(F)cc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 4-nitro-2,6-difluoro-phenol (5.08 g, 29.0 mmol) and cesium carbonate (10.3 g, 31.7 mmol) in 100 mL acetonitrite was treated with methyl bromoacetate (3.0 mL, 31.7 mmol). The mixture was heated at reflux for 2 h. The mixture was allowed to cool to ambient temperature, and partitioned between water and ethyl acetate. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated to afford material which was purified by silica gel chromatography eluting with hexane: ethyl acetate (2:1). Concentration of the relevant fractions afforded the title compound (6.11 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH2:9](N(CC)CC)C.ClCCN=C=S>ClCCl>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: CCN(CC)CC
Reactant: OC[C@@H]1CSC(S)=N1
Agent: S=C=NCCCl
Solvent: ClCCl
Product: CSC1=N[C@H](CO)CS1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 3-hydroxyazetidine hydrochloride (5) was cooled to 0° C. in the stream of nitrogen, and, to this solution, there were added 0.31 ml of triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride containing 250 mg of chloroethylisothiocyanate dissolved therein, and the resultant solution was stirred for 30 minutes at the same temperature, and, after left still until it had a room temperature, the solution was further stirred for two hours. Next, dichloromethane was added to the reaction liquid, and the resultant solution was washed with a saturated aqueous solution of potassium carbonate, and, thereafter, the dichloromethane layer was dried with magnesium sulfate, and then was condensed under reduced pressure, and, thus, there was obtained 300 mg (yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless needle crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](Cl)=[O:20])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.CCCCCC.C([O:55]C(=O)C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:55])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCO
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: CN(C)c1ccccn1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
2-benzyloxynaphthalene-6-carboxylic acid chloride (6.4 g) was dissolved in 50 ml of methylene chloride and added in small portions to a solution of 1-octanol (2.6 g), dimethylaminopyridine (0.7 g) and triethylamine (2.1 g) in 30 ml of methylene chloride under ice-cooling. After the reaction mixture was stirred for about 20 hours, it was poured into ice-water and extracted with methylene chloride. The solvent was removed by evaporation to give a crude product, which was then subjected to silica gel column chromatography (eluent: hexane/ethylacetate=10/0.5) to give 2.6 g of 2-benzyloxy-6-octyloxycarbonylnaphthalene.