Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OC1C=[CH:40][C:39]([Cl:42])=[CH:38]C=1)=O.ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:23]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:40][C:39]([Cl:42])=[CH:38][CH:29]=4)=[O:25])[CH2:22]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccc(Cl)cc4)C3)cc2=O)cc1

Procedure:
Example 18 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 4-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.25 Hz, 2H), 7.61 (d, J=8.25 Hz, 2H), 7.32 (d, J=8.80 Hz, 2H), 7.25 (dd, J=7.70, 3.30 Hz, 1H), 7.09 (d, J=8.80 Hz, 2H), 6.06-6.12 (m, 1H), 5.98-6.03 (m, 1H), 3.92-4.09 (m, 2 H), 3.49-3.92 (m, 3H), 3.34-3.48 (m, 1H), 3.09 (s, 3H), 2.73-2.89 (m, 1H), 2.12-2.29 (m, 1H), 1.79-1.97 (m, 1H). MS (ESI) 503 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 22: (+)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol), triethylamine (13.1 μL, 0.093 mmol), tetrahydrofuran (2 ml) and iodoethane (5.6 μL, 0.07 mmol). The crude product analyzed by GCMS. Analysis showed 92% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 6), 226 (46), 211 (23), 141 (43), 71 (bp).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1.[NH4+].[Cl-]>CO.C(O)(=O)C>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CCC=CN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of diethyl ethoxymethyleneoxalacetate (43.2 g, 0.16 mol) dissolved in CH3OH (150 mL) at -10° under N2 is added 1-morpholinobutene (25 g, 0.16 mol). The reaction is slowly warmed to room temperature over three hours, after which the CH3OH is removed in vacuo. The residue is dissolved in acetic acid (100 mL) and this solution slowly added to NH4Cl (34.2 g, 0.64 mol) dissolved in acetic acid (200 mL) at 50°-70°. The reaction is then heated to 90°-95° for two hours and 30 minutes, concentrated in vacuo, partitioned between water and the CH2Cl2, and the organic phase chromatographed over silica gel with CH2Cl2 -CH3CN (95:5) elution to give the product as an oil. Distillation at 123°-155° at 0.15mm gives the product (23.4 g, 83% pure, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][OH:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:17][CH:18]=1)(=[O:21])[CH2:19][OH:22]
Reactant: O=C1Nc2ncccc2C1=Cc1ccc(O)cc1
Reactant: O=C(Cl)CO
Solvent: c1ccncc1
Product: O=C(CO)Oc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 3-(4-hydroxybenzylidene)-7-azaoxindole (2,383 g. 10 mmol) in pyridine (10 ml) was added gradually glycoloyl chloride (0.945 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 4 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 60% yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (5 g, 8.65 mmol) in DMF (15 mL) was added N-iodosuccinimide (1.86 g, 8.27 mmol) and the resulting mixture was allowed to stir at room temperature for 1 hour. The mixture diluted with EtOAc (100 mL), washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL) once, and combined organic layer was washed with water (20 mL) three times, brine once and dried (MgSO4). After concentration, the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hex (0-30%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (4.55 g, 75%).
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.O=C1CCC(=O)N1[O:26][C:27](=O)[CH2:28][C:29]#[N:30].C(O)C>>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:27](=[O:26])[CH2:28][C:29]#[N:30])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]ccc12
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 182.5 %

Procedure:
A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product.
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C>CCO.N.O.[Ni]>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[N:9]=[C:8]([NH:7][C:6](=[O:5])[OH:22])[CH:13]=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: NCc1ccc(-c2cccc(NC(=O)O)n2)cc1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid ten-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3H), 7.70 (t, J=7.8 Hz, 1H), 7.33-7.40 (m, 4H), 3.92 (brs, 2H), 1.53 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1

Procedure:
Under an argon atmosphere, to a solution of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (2.12 g, 7.96 mmol) in CH2Cl2 (10 mL) was added DMF (3 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (1.35 mL, 16.0 mmol) at 0° C. and the mixture was stirred for an hour while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20](O)=O)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1.N>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(O)C>[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20]3[NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[N:8]=3)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1
Reactant: Nc1ccccc1N
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)Nc2cc(-c3nc4ccccc4[nH]3)ccc21
Yield: 37.2 %

Procedure:
One stirs ortho-phenylenediamine (1.30 g, 12.0 mmol) and 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (2.60 g, 12.0 mmol; preparation see DE-A-3,818,830) in a mixture of polyphosphoric acid (50 g) and diphosphorus pentoxide (10 g) for 3 hours at 160° C. One allows to cool to 80°-90° C., carefully adds ice and water thereto and filters off the precipitate with suction. One takes up in water (200 ml), adds conc. ammonia thereto, filters off with suction, dissolves the residue in hot ethanol, filters and allows to crystallise. One dries the colourless crystals at 120° C. in a vacuum and obtains 1.30 g (37%) of the title compound with the m.p. 314°-316° C. which, per mole, still has adhering a half mol of water.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14](=O)[CH3:15].[BH4-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:14][CH3:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1 eq, 5.37 mmol) in methanol (20 mL) was added acetaldehyde (0.95 eq) and the resulting mixture was heated to 80° C. and stirred for 2 h., then stirred at room temperature overnight. Sodium borohydride (0.95 eq, 5.1 mmol ) was added and reaction mixture was stirred for an additional 2 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.05 (3H, t), 1.45 (9H, s), 1.60-1.75 (1H, m), 2.00-2.10 (1H, m), 2.68 (4H, q), 2.90-3.15 (1H, m), 3.25-3.65 (4H, m). ESI-MS m/z: 215 (M+1), UV retention time: 0.75 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:14](=[O:16])[CH3:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)[CH:10]=1)=[O:16]
Reactant: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1cc(-c2ccc(C(F)(F)F)cc2)cs1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:31]([C:34]1[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1)([CH3:33])[CH3:32]>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([CH:31]([CH3:32])[CH3:33])[N:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: CC(C)c1cn(CC(=O)O)nn1
Product: CC(C)c1cn(CC(=O)Nc2cncc(C(=O)c3cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c4ccncc34)c2)nn1

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and (4-isopropyl-[1,2,3]triazol-1-yl)acetic acid. LCMS (5 minute run) Rt=3.32 minutes MS m/z 576 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:6][CH2:7]2.ClN1C(=O)CCC1=O.[OH-].[K+].O>C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[N:6]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Dissolve (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g, 11.8 mmol) in diethyl ether (118 mL). Add N-chlorosuccinimide (2.36 g, 17.7 mmol). Stir 30 min at room temperature and concentrate under reduced pressure. Dissolve the residue in potassium hydroxide (42.0 mL, 30.3 mmol, 5% in MeOH) and stir for 30 min at room temperature. Pour into water and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-100% gradient) to give the title compound (3.40 g, 9.59 mmol). MS (m/z): 354 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2:15][C:16]1C=CC=C[CH:17]=1.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]=[CH:16][NH:15]1
Reactant: Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C1=Cc2ccccc2ON1
Yield: 80.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, aniline and formalin were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, water, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 80.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20]
Reactant: CC(C)CI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2CC(C)C)c(OC)c1
Yield: 12.7 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 1-iodo-2-methylpropane (0.23 mL, 2.00 mmol) to give the title compound (0.046 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC2)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride (11.8 g) was added dropwise to a stirred mixture of 5-aminoindan (9.0 g), potassium carbonate (9.3 g), ethyl acetate (90 ml) and water (90 ml) under ice-cooling. The mixture was further stirred under ice-cooling for one hour, at the end of which time the organic layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The procedure gave crystals of 5-(2-chlorobenzoylamino)indan. The crystals were collected by filtration and recrystallized from isopropyl ether to give colorless needles, m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4](I)[CH:3]=1.[Cu][C:12]#[N:13]>CC(N(C)C)=O>[NH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[C:12]#[N:13]
Reactant: Nc1cc(F)c(Cl)cc1I
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Cl)c(F)cc1N
Yield: 78.4 %

Procedure:
A solution of 4-chloro-5-fluoro-2-iodo-phenylamine (2.5 g, 9.21 mmol) and copper (I) cyanide (1.65 g, 18.4 mmol) in DMA (45 ml) was heated to 130° C. overnight. Most of the DMA was removed under reduced pressure and the remaining residue was diluted with EtOAc and dichloromethane. The slurry was filtered and the filter cake was washed with dichloromethane and EtOAc. The filtrate was concentrated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-85:15) to afford the title compound (1232 mg, 78%) as light red solid. MS (ESI): 169.2 (M−H)−.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18]Cl.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([N:14]1[CH2:18][CH2:17][CH2:16]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: c1ccc(C(c2ccccc2)N2CCC2)cc1

Procedure:
Step 1, heating benzhydrylamine and 1-bromo-3-chloropropane in admixture with butanol, water and potassium carbonate to give N-benzhydrylazetidine and separating said N-benzhydrylazetidine therefrom;
Reaction SMILES: [OH2:1].O.O.[N+]([O-])(O)=O.[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][C:16](=[O:21])[CH2:17]2)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][CH:17]2[C:16]([OH:21])=[O:1])(=[O:10])[CH3:9]
Reactant: O
Reactant: CC(=O)OC1CCC2CC(=O)CCC21
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)OC1CCC2C(C(=O)O)CCC12
Yield: 12.2 %

Procedure:
Thallic nitrate trihydrate (133 g) was added to a stirred solution of 7-acetoxybicyclo[4,3,0]nonan-3-one (57 g; prepared as described in Reference Example 4) in glacial acetic acid (290 ml). After 30 minutes the resulting solid was filtered off and the filtrate was heated at reflux for 30 minutes. The acetic acid was distilled off under reduced pressure and the residue was neutralised by treatment with aqueous sodium hydroxide solution to pH 5 and then with aqueous sodium bicarbonate solution to neutral. The resulting solution was washed with diethyl ether, and then it was acidified by treatment with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were washed with saturated aqueous sodium chloride solution, then dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate, hexane, and acetic acid (45:55:1 by volume), to give 6-acetoxy-2-carboxybicyclo[3,3,0]octane (7.55 g), predominantly in the 2β-configuration.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][CH:22]([OH:27])[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1.[C:30](OCC)(=[O:34])[C:31]([CH3:33])=[CH2:32].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([N:19]3[C:20]([CH3:29])([CH3:28])[CH2:21][CH:22]([O:27][C:30](=[O:34])[C:31]([CH3:33])=[CH2:32])[CH2:23][C:24]3([CH3:25])[CH3:26])[N:8]=2)[CH2:5][CH2:6]1
Reactant: C=C(C)C(=O)OCC
Reactant: CC1(C)CC(O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
10.2 g of 2,4-dimorpholino-6-(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 34) are heated to 120° together with 6.9 ml of ethyl methacrylate, 0.04 g of 2,6-bis-tert-butyl-p-cresol and 0.04 ml of tetrabutylorthotitanate (monomer), some liquid slowly being removed by distillation. The mixture is allowed to react for 50 hours, some ethyl methacrylate and catalyst subsequently being added periodically. After the reaction has ended, the product is filtered through bleaching earth and evaporated. The residue is dissolved in toluene/acetone and purified chromatographically on an SiO2 column, the above product being obtained as a colorless resin.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CS(C)=O>O>[C:5]([C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(F)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 143.1 %

Procedure:
A mixture of 3-fluorobenzonitrile (3.0 g, 25 mmol), piperazine (11.8 g, 137 mmol) and dimethylsulphoxide (20 ml) is heated at 100° C. for 48 hours under an atmosphere of nitrogen. The reaction mixture is then cooled, poured into water (200 ml) and the resultant precipitate collected. This solid is chromatographed on silica gel (dichloromethane) to give the title compound as a white solid (6.7 g). 1H NMR (DMSO, 500 MHz) δ7.15-7.40 (m, 4H), 3.28 (m, 3H), 3.12 (m, 1H), 2.80 (m, 1H), 2.59 (m, 3H).