Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[N:18]=[CH:19][C:12]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:26][C:25]1[C:20]([N:17]2[C:13]3=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]4[CH2:8][CH2:7][O:6][C:5]4=[O:9])=[C:12]3[CH:19]=[N:18]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCC[C@@H]1Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
60% Sodium hydride in mineral oil (0.470 g, 11.75 mmol) was added to (S)-3-hydroxydihydrofuran-2(3H)-one (0.764 mL, 9.80 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (CAS no. 52079-23-9) (2.87 g, 10.77 mmol) was added portionwise maintaining the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), water (75 mL) dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (1.970 g, 61%). 1H NMR (400 MHz, CDCl3) 2.52-2.62 (1H, m), 2.92-3.00 (1H, m), 4.41-4.47 (1H, m), 4.59-4.64 (1H, m), 6.11-6.16 (1H, m), 7.46-7.49 (1H, m), 8.00-8.02 (1H, m), 8.37 (1H, s), 8.61-8.63 (1H, m), 8.64 (1H, s); m/z (ESI+) (M+H)+=332; HPLC tR=1.51 min.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:33]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:52])[CH2:50]Cl)[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:33]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:49](=[O:52])[CH2:50][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:12])[N:3]([CH2:1][CH3:2])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[CH:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=4)[CH2:22]3)=[CH:10][CH:9]=2)[CH2:47][CH2:48]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(CCl)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)c1ccc(OCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 137.2 %

Procedure:
To a solution of N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (1.0 g) and 4-(2-chloroacetyl)piperazine-1-carboxylic acid benzyl ester (830 mg) in N,N-dimethylformamide (20 ml) was added cesium carbonate (1.0 g), and the solution was stirred for 1 hour at 60° C. To the reaction solution was added brine, the solution was extracted with ethyl acetate, then dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-methanol system) to provide 4-{2-{4-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]carbamoyl}phenoxy}acetyl}piperazine-1-carboxylic acid benzyl ester (2.2 g). Synthesized from the total amount of this compound according to an analogous synthetic method to Example 22, N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-oxo-2-piperazin-1-ylethoxy)benzamide (1.5 g) was used according to an analogous synthetic method to Example 160 to provide the title compound (300 mg).
Reaction SMILES: Cl.[NH2:2][NH2:3].CCO/[CH:7]=[CH:8]/[C:9]([C:11]([F:14])([F:13])[F:12])=O.FC(F)(F)C(Cl)=O.C(OCC)=C>CO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: NN
Reactant: CCO/C=C/C(=O)C(F)(F)F
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc[nH]n1

Procedure:
To a solution of 4.4 moles hydrazine.hydrochloride in 2.2 L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel an equimolar amount of ETFBO which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether was added dropwise over about 4 hours under N2 atmosphere. The temperature of the reaction mixture was kept below 15° C. After 12 h of reflux, the reaction batch was filtered in a 2-L flask and concentrated under vacuum (an identical batch was made under the same conditions, yield of both crude products was ca. 95%). Subsequently, the combined crude product was purified by shortpass-vacuum distillation at 27 mbar. The yield was 1105 g, which corresponded to 92% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH:5]([O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[Cl:1])[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Yield: 80.7 %

Procedure:
199.5 g (0.71 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 500 ml of chloroform and 114 g (0.71 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, 200 ml of water were carefully added to the chloroform phase was washed several times with ice-water and dried over sodium sulphate. After distilling off the solvent in vacuo, 205.2 g (78% of theory) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were obtained as an oil which was further reacted directly. ##STR83##
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Cl[CH2:12][CH:13]1[O:17][CH2:16][O:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:17]1[CH:13]([CH2:12][NH:4][C:3]2[C:2]([CH3:1])=[CH:8][C:7]([Br:9])=[CH:6][C:5]=2[CH3:10])[CH2:14][O:15][CH2:16]1
Reactant: ClCC1COCO1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: Cc1cc(Br)cc(C)c1NCC1COCO1

Procedure:
2,6-Dimethyl-4-bromoaniline (0.3 mole), 5-chloromethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 5 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxolan-5-ylmethyl)-2,6-dimethyl-4-bromoaniline.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S(=O)(=O)([OH:16])N.[O-]Cl=O.[Na+]>CC#N.O>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[C:9]=1[O:10][CH3:11])[C:5]([OH:16])=[O:6]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzaldehyde (25.0 g, 85.6 mmol) in CH3CN (800 mL) at room temperature, was added a solution of sulfamic acid (10.65 g, 109 mmol) in H2O (135 mL). To this was added, dropwise, a solution of NaClO2 (12.65 g, 112 mmol) in H2O (135 mL) over 20 min period. After stirring for a further 30 min at room temperature, the solvent was removed in vacuo. The reaction was diluted with 1.0 M aqueous HCl (700 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-iodobenzoic acid (26 g). The product was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH:33]4[CH2:35][CH2:34]4)=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH:33]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)[N:19]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:5][N:6]=1.Cl.[OH-].[K+]>C(O)C.[Fe]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2cccc([N+](=O)[O-])c2)o1
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1nnc(-c2cccc(N)c2)o1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
Iron powder, 27.9 g (0.5 mol), is added to a mixture of 2-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazole, (0.053 mol), in 1000 ml of ethyl alcohol with stirring. The mixture is heated to reflux and 1.73 ml of concentrated hydrochloric acid in 10 ml of ethyl alcohol is added dropwise. The mixture is reluxed three hours, 20 ml of 1 normal potassium hydroxide is added, the mixture filtered, and the filtrate evaporated. The residue is dissolved in dichloromethane, washed with water, and the methylene chloride layer separated and evaporated to give 7.05 g of 3-(5-methyl-1,3,4-oxadiazol-2-yl) benzenamine after recrystallization from 2-propanol; mp 139°-140° C.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]=[CH:31][C:30](=O)[CH2:29]1>O1CCCC1.CCCCC>[Cl:7][CH:8]=[C:30]1[CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:28][CH2:29]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=Cc2ccccc2OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: ClC=C1C=Cc2ccccc2OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
1.1 eq. of n-butyllithium are added to 104 mg (0.3 mmol) of chloromethyltriphenylphosphonium chloride in solution in tetrahydrofuran cooled to 0° C. After stirring for one hour, 40 mg (0.25 mmol) of 1-benzoxepin-3(2H)-one, prepared according to example 25, are added at ambient temperature and the mixture is left for 1 hour. After the usual treatments and evaporating the solvent under reduced pressure, the crude reaction product is taken up in pentane in order to precipitate triphenylphosphine oxide, to give 25 mg (52%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin in the form of two isomers as a Z/E mixture (90/10); 1H NMR (300 MHz, C6D6) 6.98–6.78 (m, 4H), 6.02 (d, J=11.8 Hz, 1H), 5.80 (d, J=11.8 Hz, 1H), 5.68 (s, 1H), 4.65 (4.06) (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9]([N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH2:8]1
Reactant: O[C@H]1CC[C@@H](c2ccccn2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A solution of cis-3-(2-pyridyl)cyclopentanol (1.86 g, 11.4 mmol) in THF (100 mL) was cooled to 0° C. and treated with phthalimide (1.85 g, 12.5 mmol), diethylazodicarboxylate (2.2 M in toluene, 5.7 mL, 11.4 mmol) and triphenylphosphine (3.29 g, 12.5 mmol). The reaction mixture was stirred at room temperature for overnight. The solvent was removed, and the crude product was purified by column chromatography (Hexane/EtOAc=3/1→2/1→1/1) to yield trans-N-[3-(2-pyridyl)cyclopentyl]phthalimide (1.52 g, 41%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNC1CCCCC1.C(O)C>[CH:22]1([N:23]([CH3:26])[CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH2:4]1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CNC1CCCCC1
Solvent: CCO
Product: CN(C[C@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)C1CCCCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylcyclohexylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1C=O.OO.C1CCCCC1.CC[O:22]C(C)=O>[OH-].[Na+].CCOC(C)=O>[OH:22][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:2]=1[OH:1]
Reactant: CCOC(C)=O
Reactant: CCc1cccc(C=O)c1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Product: CCc1cccc(O)c1O
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a solution of crude 9 (ca. 80 mmol) in 2N NaOH (40 mL) cooled to 0-5° C., a solution of ca. 7% hydrogen peroxide (49 mL) was added dropwise over 30 min while maintaining the temperature at 20° C. The reaction was stirred for further 45 min then diluted with AcOEt (ca 250 mL), washed with HCl 2N (ca 50 mL). The aqueous layer was e-extracted with AcOEt and the combined organic extracts were washed with brine, and dried over sodium sulphate. The solvent was removed under reduced pressure to give a crude which was columned (cyclohexane:AcOEt 4:1) to give 6.4 g of 10 as a brown oil:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].C1COCC1.[OH-].[Na+].[N+:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CCO>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([C:29](=[O:30])[C:28]2[CH:39]=[CH:40][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (2.03 g, 9.74 mmol) in EtOH (30.0 ml)-THF (30.0 ml) was added 1N-aqueous sodium hydroxide solution (10.0 ml). Then, 4-(4-nitrobenzoyl)benzyl bromide (3.50 g, 10.9 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from methanol to provide light-yellow needles.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][CH:16]([CH3:26])[CH2:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)C>[CH3:15][CH:16]([CH3:26])[CH2:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CC(C)COc1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 2-(2-methylpropoxy)aniline (45 g) is heated with stirring at 120° C. for 2 hours. After cooling, ethanol (300 ml) is added to the reaction mixture and the solid is pulverized, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (57 g). M.p. 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][C:23]([N:37]2[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]2)=[O:24])=[O:20])=[CH:26][CH:27]=1)(=[O:14])=[O:13]
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 562.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)(=[O:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)oc2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Cn1c(=O)oc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of methyl 2-(6-amino-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.497 g, 2.237 mmol) in pyridine (15 ml) was cooled to 0° C., and methanesulfonyl chloride (0.209 ml, 2.68 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. The solvent was removed and the residue was portioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate; the solvent was removed and the crude was purified by trituration with diethyl ether affording methyl 2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.523 g, 1.742 mmol, 78% yield). MS/ESI+ 300.9 [MH]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:36])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:23][CH2:22]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:36])[NH:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:25][CH2:26]3)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:4]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: COc1ccccc1CN1CCC(NC(=O)CN(Cc2cc(C=O)ccn2)C(=O)OC(C)(C)C)CC1
Product: COc1ccccc1CN1CCC(NC(=O)CN(Cc2cc(CNC3CC3)ccn2)C(=O)OC(C)(C)C)CC1

Procedure:
By General Procedure A from tert-butyl N-[(4-formylpyridin-2-yl)methyl]-N-[({1-[(2-methoxyphenyl)methyl]piperidin-4-yl}carbamoyl)methyl]carbamate and cyclopropylamine. Purification by column chromatography (CH2Cl2/MeOH/NH4OH, 90:10:1) gave the title compound as a colorless glue. 1H NMR (300 MHz, CDCl3): δ 9.40 (br s, 1H), 8.62 (2S, 1H; rotamer), 8.40 (s, 1H), 7.50-7.40 (m, 2H), 7.38 (m, 1H), 7.20 (m, 1H), 7.00-6.80 (m, 2H), 4.58 & 4.48 (2S, 2H; rotamer), 4.00-3.60 (m, 8H), 3.18-2.99 (m, 4H), 2.40-2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.40 & 1.20 (2S, 9H; rotamer), 1.00 (m, 4H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:53][C:54]1[N:59]=[CH:58][N:57]=[C:56]2[N:60]([C:63]3[C:68]([Cl:69])=[CH:67][CH:66]=[CH:65][N:64]=3)[N:61]=[CH:62][C:55]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:69][C:68]1[C:63]([N:60]2[C:56]3=[N:57][CH:58]=[N:59][C:54]([O:53][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=4)=[O:43])=[C:55]3[CH:62]=[N:61]2)=[N:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.139 mL, 0.14 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide (Intermediate AB1) (100 mg, 0.14 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with DCM (10 ml) and poured onto a phase separator. The organic layer was collected and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (38.0 mg, 56.8%). 1H NMR (300 MHz, CDCl3) δ 2.36 (1H, s), 3.70-3.86 (4H, m), 4.16-4.27 (2H, m), 6.07 (1H, t), 7.45-7.52 (1H, m), 7.93-8.05 (2H, m), 8.32-8.38 (1H, m), 8.46 (1H, s), 8.55-8.58 (1H, m), 8.60-8.65 (2H, m), 9.28 (1H, s). m/z (ES+) (M+H)+=481.31; HPLC tR=1.63 min.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[OH-].[NH4+:19]>C(O)C>[NH2:19][C@@H:7]1[C:6]2[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]([CH3:17])([CH3:16])[C@H:2]1[OH:1]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (4.0 g), ammonium hydroxide (containing ca. 28% ammonia, 40 ml), and ethanol (20 ml) was stirred at room temperature for 72 hours. The reaction mixture was concentrated, added to diisopropyl ether, and pulverized to give trans-4-amino-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (4.0 g).