Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([O:17][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2cccc(OCc3ccccc3)c2)nc1Nc1cccc(OCc2ccccc2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-benzyloxyaniline were reacted to yield N2,N4-bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.98 (bs, 1H), 7.42-6.99 (m, 16H), 6.75 (d, 1H, J=2.4 Hz), 6.71 (m, 1H), 6.60 (dd, 1H, J=2.4 and 8.4 Hz), 6.32 (m, 1H), 4.97 (s, 2H), 4.94 (s, 2H); LCMS: ret. time: 32.56 min.; purity: 98%; MS (m/e): 493 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[CH3:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41])[N:25]=[CH:24][N:23]=[C:22]2[S:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCOC
Temperature: 90 °C

Procedure:
As described in Example 50, a mixture of the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.117 g, 0.4 mmol), 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (0.125 g, 0.4 mmol) from Example 12A, and Cs2CO3 (0.20 g, 0.6 mmol) in isopropanol (5 mL) was heated at 90° C. overnight, to afford 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)urea. as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.99 (s, 1H), 8.68 (s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.46 (t, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.28 (dd 1H), 6.49 (s, 1H), 4.34 (m 4H), 3.78 (m, 4H), 3.37 (s, 3H), 3.35 (s, 3H), 1.28 (s, 9H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=S.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[CH:13]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][C:2]2=[N:16][N:15]=1
Reactant: S=C1CCNc2ccccc2N1
Reactant: NNC=O
Solvent: CCCCO
Product: c1ccc2c(c1)NCCc1nncn1-2
Yield: 37.3 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formyl-hydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165° C.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11]1C=CC=CC=1.S(=O)(=O)(O)O>CO>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccnc1O
Reaction time: 8 h
Yield: 22 %

Procedure:
2-Hydroxynicotinic acid (6.95 g, 50 mmol) was dissolved in 125 mL of methanol, 75 mL of benzene, and 0.75 mL of concentrated sulfuric acid under nitrogen and heated at reflux for 2.5 hours. A Dean-Stark trap was added to the apparatus and heating was continued overnight. The volatiles were removed under reduced pressure and the resulting solid was suspended in cold water (150 mL) and filtered to remove unreacted starting material. The filtrate was extracted with methylene chloride and chloroform. The combined organic extracts were concentrated in vacuo to afford 2.5 g. Recrystallization from hot benzene afforded 1.7 g (22%) of the title compound. 1H NMR (CD3OD, 300 MHz) δ 3.83 (s, 3H), 6.45 (t, 1H), 7.68 (dd, 1H), 8.29 (dd, 1H). MS (DCl/NH3) m/e 154 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1)[CH3:12].CC(C)CC(=O)C>O>[CH3:12][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=1)[CH3:10]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45°-50°. 2-[[[5-(Dimethylamino) methyl-2-furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 31/2 hr. The solution was then heated at reflux for 1/2 hr., cooled to 70° and 4-methylpentan-2-one (2 liters) added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resultant solution treated with charcoal (10 g) at 50°. The solution was filtered and cooled to 10°. N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried m.p. 69°-70°.
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH:12]1[CH2:17][CH2:16][N:15](C)[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:11][CH:12]1[CH2:17][CH2:16][N:15]([C:1]([O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(Cl)CC1
Reaction time: 6 h
Yield: 71.3 %

Procedure:
A solution of phenyl chlorocarbonate (17.3 g) in dry methylene chloride (40 ml) was dropwise added to a stirred solution of 4-chloro-1-methylpiperidine (13.3 g) in dry methylene chloride (60 ml) under ice-cooling over a period of 5 minutes. The resultant mixture was stirred at the same temperature for 30 minutes and then at room temperature for 6 hours. The mixture was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give an oil, which was distilled to give phenyl 4-chloro-1-piperidine-carboxylate (17.0 g) as a colourless oil.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(N)ccc2O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC1CCc2cc(NC(C)=O)ccc2O1
Reaction time: 0.5 h

Procedure:
The ethyl 2-(6-aminochroman-2-yl)acetate toluene solution of Example 4 (6 L) was cooled to −5° C. in a sodium chloride-ice bath, and 293 g of anhydrous pyridine added in a single portion. To the well-stirred mixture was added dropwise 246 g of acetyl chloride, maintaining the temperature between −5° C. and 5° C. The reaction was not complete by TLC after 30 min, so an additional 50 g of anhydrous pyridine and 50 g of acetyl chloride were added dropwise, and the reaction stirred for 30 min. The reaction was quenched with 4 L of water, stirred for 15 minutes, and the organic fraction was separated. The aqueous fraction was extracted with 2×500 mL of toluene, and the combined toluene fractions washed with 2 L of water. Complete removal of toluene afforded ethyl 2-(6-acetamidochroman-2-yl)acetate as a dark brown residue, which was transferred into a 12-L flask.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21](F)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC(Cl)=CC=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[C:20]([Cl:31])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1cc(Cl)ccc1Cl
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1cc(Cl)ccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=442 @ Rt 3.48 min. major peak.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:17](=[N:20][O:21][CH2:22][CH:23](O)[CH3:24])([CH3:19])[CH3:18].[Na]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH:23]([CH3:24])[CH2:22][O:21][N:20]=[C:17]([CH3:19])[CH3:18])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)=NOCC(C)O
Reactant: O=C([O-])COc1ccc(Cl)c2cccnc12
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)=NOCC(C)OC(=O)COc1ccc(Cl)c2cccnc12
Temperature: 50 °C
Yield: 51.3 %

Procedure:
4.75 g (0.02 mol) of 5-chloroquinolin-8-oxyacetate are suspended in 50 ml of tetrahydrofuran, 3.2 g (0.02 mol) of N,N'-carbonyldiimidazole are added and the suspension is heated to 50° C. until the evolution of gas has ended. A solution of 2.62 g (0.02 mol) of 1-isopropylideneaminooxy-2-propanol and 50 mg of sodium in 10 ml of tetrahydrofuran (THF) is added dropwise to this suspension and the mixture is heated under reflux. After the reaction, the THF is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the solution is washed with 5% strength NaOH and NaCl solution. The organic phase is dried over MgSO4 and concentrated and the residue is recrystallized from heptane. 3.6 g (45.6% of theory) of 1-isopropylideneaminooxy-2-propyl 5-chloroquinolin-8-oxyacetate of melting point 102° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C=Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-4-methyl-pent-1-en-3-one (Compound 14, 7.98 g, 31.7 mmol) in 20 mL diethyl ether at 0° C. was slowly added lithium aluminum hydride (LAH) (1.20 g, 38.0 mmol). After stirring for one hour and subsequent warming to room temperature the reaction was quenched by 2 mL of saturated ammonium chloride solution at 0° C. with an ice bath and dried over anhydrous MgSO4. Solid was removed by filtration and the filtrate was concentrated at reduced pressure to obtain a crude colorless oil. 5 g of polyphosphoric acid (PPA) was then added to the crude oil and the mixture was heated at 120° C. for 15 min. After cooling to room temperature, the mixture was taken up in water (100 mL), extracted with diethyl ether (3×15 mL), washed with brine (1×15 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) afforded the title compound (6.70 g, 89% yield) as a light yellow oil:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1.C(N(CC)CC)C.[F:27][C:28]([C:73]([F:76])([F:75])[F:74])([O:32][C:33]([F:72])([F:71])[C:34]([F:70])([C:66]([F:69])([F:68])[F:67])[O:35][C:36]([F:65])([F:64])[C:37]([F:63])([C:59]([F:62])([F:61])[F:60])[O:38][C:39]([F:58])([F:57])[C:40]([F:56])([C:52]([F:55])([F:54])[F:53])[O:41][C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[C:29](F)=[O:30]>>[F:27][C:28]([C:73]([F:74])([F:75])[F:76])([O:32][C:33]([F:71])([F:72])[C:34]([F:70])([C:66]([F:67])([F:68])[F:69])[O:35][C:36]([F:64])([F:65])[C:37]([F:63])([C:59]([F:62])([F:61])[F:60])[O:38][C:39]([F:57])([F:58])[C:40]([F:56])([C:52]([F:55])([F:54])[F:53])[O:41][C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[C:29]([O:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1)=[O:30]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCO)O[Si](C)(C)O1
Solvent: CCN(CC)CC
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCOC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)O[Si](C)(C)O1
Yield: 71.8 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 6.2 g of 98% (3-hydroxypropyl)heptamethylcyclotetrasiloxane (18 mmoles) and 1.8 g of triethylamine (18 mmoles). The mixture was stirred and 15.0 g of 95% perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecanoyl fluoride (17 mmoles) was added dropwise. After complete addition of the acid fluoride a gas chromatographic analysis indicated that essentially all of the acid fluoride and most of the cyclosiloxane were consumed with predominately the formation of one product. A 25 mL portion of dilute hydrochloric acid was added to the flask and the two phase mixture was transferred into a separatory funnel and the aqueous layer was separated from the siloxane layer. The siloxane layer was washed with two 25 mL portions of water and the siloxane layer was transferred into a 50 mL round bottom flask and distilled at 118-28° C. and 0.05 mmHg to yield a fraction of 14.0 g (71% yield) of 99% [3-(perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecan-oyl)oxypropyl]heptamethylcyclotetrasiloxane (12.2 mmoles), which corresponds to formula (I) wherein m is 1, n is 3, X is OC(O), and RF is given by formula (II) wherein p is 4, or more specifically as shown in formula (VII) wherein p=4. The product was analyzed by spectroscopy with the following results: 1H NMR 400 MHz, CDCl3 : d 0.1 (s 21 H), 0.6 (t 2 H), 1.8 (p 2 H), 4.4 (m 2 H); IR (neat liquid on NaCl): cm 2970 (m), 1780 (s), 1245 (vs), 1200 (s), 1145 (s), 1070 (vs), 995 (s), 970 (s), 810 (vs), 750 (m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:5]2=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[C:23]1([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[C:5]3=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Reactant: OB(O)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cnc3c(c2)ncn3-c2cccc(-c3cccnc3)c2)cc1

Procedure:
The title compound was prepared from 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine and phenylboronic acid as described in Example 1. Free base, white powder, m.p. 179-180° C. (from ethanol); δH (400 MHz, CDCl3) 7.41-7.44 (1H, m), 7.52 (2H, t, J 7), 7.65-7.74 (4H, m), 7.83 (1H, d, J 8), 7.97 (1H, d, J 8), 8.07 (1H, s), 8.35 (1H, d, J 2), 8.44 (1H, s), 8.49 (1H, s), 8.65 (1H, d, J 5), 8.72 (1H, s), 8.95 (1H, s); m/z (ES+) 349 (M++H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:15])=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C(N)=O)CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2O)CCC1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To 1-(2-methoxyphenyl)cyclobutanecarboxamide (Example 268a, 4.19 g) at 0° C. in dichloromethane (20 mL) was aded boron tribromide (40.8 mL, 1M in dichloromethane) and the reaction warmed to room temperature over 3 h. It was poured into ice, extracted with dichloromethane (×3) and the combined organics were dried (MgSO4) and the solvent was removed in vacuo to give crude 1-(2-hydroxyphenyl)cyclobutanecarboxamide (2.96 g). This was dissolved in DMF (20 mL) and potassium carbonate (2.14 g) and benzyl bromide (1.84 mL) were added and the reaction stirred for 16 h. Water and ethyl acetate were added and the organic layer separated. The aqueous layer was extracted further with ethyl acetate. The combined organics were washed with water (×3), brine, dried (Na2 SO4) and the solvent was removed in vacuo. The residue was purified (SiO2 chromatography eluting with 5-50% ethyl acetate in iso-hexane) to afford the subtitle product (1.98 g).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[C:19]1([N+]#N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)C>[C:1]1([C:7]([CH2:9][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#[N+]c1ccccc1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
0.97 mmol of (1-phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The resulting mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5 N hydrochloric acid, water and a saturated aqueous solution of common salt, successively. The organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.68 mmol of benzyl phenyl ketone.
Reaction SMILES: C([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[O:22])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[NH:3][CH2:4][CH2:5][C:6]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)=[O:22])=[CH:7][C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1177 mg) was added 1N hydrochloric acid (20 ml), and the mixture was stirred at 100° C. for 1 hour. The mixture was dilute with ethyl acetate(50 ml) and made weakly basic with saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml), and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) to give 7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 318) (804 mg, 72%) as amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([O:26]CC)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (2.24 mmol) of ethyl 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in a mixture of 15.5 ml of dioxane and 7.7 ml of water, 215 mg (8.97 mmol) of lithium hydroxide were added and the mixture was stirred at RT overnight. For workup, the reaction solution was concentrated under reduced pressure, then water was added and the mixture was acidified with 1N hydrochloric acid. The precipitate formed was filtered off, washed and dried under reduced pressure. The filtrate was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The two solids gave a total yield of 764 mg (95% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 92.8 %

Procedure:
(R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (7D) (0.387 mmol, 0.120 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.387 mmol, 0.127 g) and N-methylmorpholine (1.55 mmol, 0.170 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.426 mmol, 0.162 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (7E) as a clear oil (0.359 mmol, 0.210 g, 93% yield). ESI-MS: m/z 585.5 (M+Hr.