Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[O:18])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:25])[NH2:24].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:25])[NH:24][C:17]([NH:16][CH2:15][C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([C:10](=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:11])[CH:13]=1)=[O:18]
Reactant: CN(C)N
Reactant: CC(=NOCc1ccccc1)c1cccc(CN=C=O)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=NOCc1ccccc1)c1cccc(CNC(=O)NN(C)C)c1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of 2.75 g of crude 3-(1-(benzyloxyimino)ethyl)benzylisocyanate in 13 ml of dry toluene was added dropwise a solution of 0.53 g (8.74 mmol) of N,N-dimethylhydrazine in 5 ml of dry toluene with ice-cooling. The mixture was removed from an ice bath and stirred for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 0.55 g (1.62 mmol) of 1,1-dimethyl-4-{3-(1-(benzyloxyimino)ethyl)benzyl}-semicarbazide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][O:10]C2=O)[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH:8][C:6]2[CH:5]=[C:4]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH2:11][OH:10])=[CH:18][CH:17]=1
Reactant: Nc1cnccn1
Reactant: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Nc3cnccn3)nc(NC(CO)c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 22 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2.5 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:15]([C:23](O)=[O:24])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:29][CH:28]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:39]=[C:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]([C:15]2[CH:16]=[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-furan-2-yl-1H -pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 62 mg 4-(4-Amino-phenyl)-morpholin-3-one and 67 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH:9]=[O:10])[S:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[N:4]=1)=[O:10]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=CNc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
A mixture of 4-chloromethyl-2-formylaminothiazole (1.76 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (1.8 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. with stirring. The reaction mixture was poured into ice-water and stirred at 5° C. for an hour. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.3 g, yield: 78%). mp: 158°-160° C. IR (Nujol): 3500, 1680, 1595, 1550, 1330 cm-1
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.Cl.[OH-:22].[Na+].[OH2:24]>>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:17]([O-:24])(=[O:22])[CH3:18]
Reactant: O
Reactant: [OH-]
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cl
Agent: [Na+]
Product: CC(=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sertraline hydrochloride (125 g) was slurried in a mixture of water (1 L) and (2.5 L). NaOH (25% aqueous, 35 mL) was added. Sertraline base partitioned into the hexane phase. The hexane layer was separated. The aqueous layer was extracted a second time with hexane (500 mL). The hexane layers were combined. The solution of sertraline base in hexane was heated to 50° C. Glacial acetic acid (23 ml) was added to the solution of sertraline base. The reaction mixture was stirred at 50° C. for 30minutes. The reaction mixture was allowed to cool to room temperature and stirred at room temperature overnight. The crystals were filtered and washed five times with a total of 250 mL of hexane. The solids were dried at 40° C. in a vacuum oven for 48 hours. The yield was 89%. mp 126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:29])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH3:29])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(C)CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CC(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-(3-methylbutyryl)piperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one (114 mg, 66%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.36 min, m/z 403.46 (35), 401.44 (M++H, 100). HPLC tr=3.39 min (96.55%) 1H NMR (270 MHz, CDCl3) δ 0.92 (6H, d, J=6.4 Hz, 2CH3), 1.23 (2H, m, CH2), 1.46 (br s, NH), 1.82 (2H, br d, J=12.9 Hz, CH2), 2.05 (1H, hept, J=6.4 Hz, CHMe2), 2.19 (2H, m, CH2), 2.65 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.77 (1H, m, ½CH2), 3.79 (2H, s, CH2NH), 4.40 (1H, br d, J=13.3 Hz, ½CH2), 6.81-6.87 (3H, m, ArH), 7.11 (1H, td, ArH), 7.19-7.25 (3H, m, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 22.80 (CH2), 22.90 (CH3), 25.93 (CH), 32.30, 33.15, 40.23, 42.24, 44.44, 45.65 (CH2), 53.87 (CH), 118.93, 119.62, 124.54, 127.94, 128.71, 129.83, 130.58, 131.79, 154.34, 156.37 (ArC), and 170.91 (C═O).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)CCC.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N:19]([CH3:28])[CH3:18])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: Clc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CN(C)c1ccc(CNc2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 170 °C
Yield: 28.9 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (313 mg, 1.00 mmol) and 4-dimethylaminobenzylamine (225 mg, 1.5 mmol) in 1-butanol (20 mL) was heated to 170° C. in a 50 mL sealed tube for 3 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with 2 N sodium hydroxide, water and brine and dried over sodium sulfate. The solution was concentrated, redissolved in DMF and purified by preparative reverse phase HPLC to give the desired product (124 mg, 29%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16](O)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.S(Cl)([Cl:26])=O.CN(C)C=O>ClCCl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([Cl:26])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)Cl)C(=O)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (mycophenolic acid) (32.0 g) was dissolved in dichloromethane (250 ml), followed by the addition of thionyl chloride (25.0 ml) and dimethylformamide (0.3 ml). The reaction mixture was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid chloride as an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[N:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1cccc2ncc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide in 1.6 mL of chloroform, 84 mg of p-toluenesulfonyl chloride, 171 mg of potassium carbonate and 0.5 mL of water were added, and the mixture was stirred at room temperature overnight. The solid was filtered off, and purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1 to obtain 14 mg of 7-fluoro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: ClCC([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])=O.[OH-].[K+]>CO>[OH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14]
Reactant: O=C(CCl)OCCN1CCOCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1COCCN1CCO
Temperature: 25 °C

Procedure:
A solution of 2-(3-oxomorpholino)ethyl 2-chloroacetate (400 g, 1.81 mol) in methanol (2 L) was added dropwise to a cooled (15° C.) solution of potassium hydroxide (203 g, 3.62 mol) in methanol (10 L). This was followed by the addition methanol (3 L). The resulting solution was allowed to react overnight while the temperature was maintained at room temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue taken up in 1 L of dichloromethane, washed with 250 ml of water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by distillation under reduced pressure (0.08 mm Hg) collecting the fraction that came over at 140° C. to afford the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH2:21]Cl)[CH:14]=1)[CH:9]=2.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:17]([CH:18]=2)=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH2:21][N:16]4[CH2:17][CH2:8][CH2:9][CH2:10][CH2:15]4)[CH:14]=2)[CH:9]=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: C1CCNCC1
Product: c1cc2cc3ccc(OCCN4CCCCC4)cc3nc2cc1OCCN1CCCCC1

Procedure:
In accordance with the above flowchart, a 3,6-bis(2-chloroethoxy)acridine (1), where R1 is as described hereinabove, is reacted with piperidine in a steel bomb at about 60° to about 1000° C. for about 18 to about 36 hours, giving a 3,6-bis(2-piperidinoethoxy)acridine (3) which is then dissolved in methanol, treated with excess 30% hydrogen peroxide for about 12 to about 48 hours, then with platinum catalyst to destroy the excess peroxide and is purified by dry column chromatography on silica gel using the developing system methanol:triethylamine (20:1, v/v). The length of reaction time with hydrogen peroxide is the determining factor in whether a mono-oxide (4) or dioxide (5) is produced.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])=[N:12][O:11][N:10]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2[C:9]([CH2:8][CH2:7][CH2:6][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:10][O:11][N:12]=2)=[O:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propyl methanesulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL,) followed by the addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction were stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified by silica gel chromatography (60-100% ethyl acetate/hexanes) to give the desired product (10.2 mg, 54%). LCMS for C16H19ClFN4O3 (M+H)+: m/z=369.1.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:34])[N:9]=[C:10]([S:32][CH3:33])[C:11](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([F:31])[CH:24]=1)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([OH:20])[C:13]=1[F:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>O>[CH3:6][O:7][C:8](=[O:34])[N:9]=[C:10]([S:32][CH3:33])[C:11](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([F:31])[CH:24]=1)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH2:42][CH2:43][O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[C:13]=1[F:21]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1cc(OC)cc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2 ml of a DMF solution containing 200 mg of [2-(4-cyano-3-fluorophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester, 300 mg of potassium carbonate and 0.2 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature for 18 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then with 5 saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give (2-(4-cyano-3-fluorophenylimino)-2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1-methylsulfanylethylidene)carbamic acid methyl ester (150 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>CS(C)=O>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:31][CH:30]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (18 mg, 0.0536 mmol), as prepared in Example 3a, 4-(2-methoxy-ethoxy)-phenylamine (8.9 mg, 0.0533 mmol), as prepared in the previous step, and triethylamine (14 μL, 0.1 mmol) was stirred in DMSO (0.5 mL) at 50° C. overnight. The reaction was then cooled to RT, partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (5.7 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.28-7.25 (m, 4H), 6.89 (m, 2H), 6.33 (br s, NH), 4.29-4.24 (m, 2H), 4.12-4.07 (m, 8H), 3.74 (m, 2H), 3.59 (m, 1H), 3.45 (s, 3H), 3.17 (m, 2H), 2.22-2.08 (m, 2H), 2.05-1.97 (m, 2H); LC/MS (ESI): calcd mass 466.2, found 467.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[N-:18]=[C:19]=[O:20].[K+].FC(F)(F)C(O)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:19](=[O:20])[NH2:18])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: NC(=O)OCc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 24 b), the reaction of [4-(3-fluoro-benzyloxy)-phenyl]-methanol with potassium isocyanate and trifluoroacetic acid in benzene yielded the carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=293 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)cc1
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccccc2OCCCCCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
1.78 g (4.63 mmol) of methyl 4-{[(tert-butoxycarbonyl)-(2-hydroxyphenethyl)-amino]methyl}benzoate from Ex.V.2, 1.05 g (4.63 mmol) of 5-phenyl-1-bromopentane and 0.77 g (5.55 mmol) of potassium carbonate in 15 ml of acetonitrile are heated at reflux for 18 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over magnesium sulphate and the solvent is distilled off under reduced pressure. A solid is obtained which is reacted further without purification.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[O:20]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:28]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4cccc(Oc5ccccc5)c4)ccc3o2)C1

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 3-phenoxy-benzoic acid (0.042 g, 0.196 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution to yield a yellow residue. Dilute with CH2Cl2 and wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo after adsorption onto silica gel. Subject the mixture to flash column chromatography on an ISCO Companion (4 g column, 10% 2M NH3 in MeOH/CH2Cl2) to yield the desired compound as a white oil. Dilute with CH2Cl2 and n-hexane and concentrate in vacuo. Pump for 2 h to yield the desired compound as a white solid (0.027 g, 45%). mass spectrum (m/e): 457.3 (M+1), 455.3 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.37-7.29 (m, 3H), 7.20-7.10 (m, 3H), 7.04-7.00 (m, 2H), 3.59-3.48 (m, 2H), 3.18 (s, 3H), 2.74-2.50 (m, 4H), 2.38-2.33 (m, 1H), 2.35 (s, 3H), 2.05-1.95 (m, 1H), 1.59-1.49 (m, 1H).