Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.O>C(O)C>[I-:1].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:9][CH:4]2[N:5]([CH3:8])[CH:6]=[CH:7][NH+:3]2[CH3:2])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
A mixture of 6.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 1g of potassium hydroxide, and 6 g of p-chlorobenzaldehyde is refluxed in 25 ml of absolute ethanol for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled, 5 ml of water is added, and the solid is filtered off and dried. Crystallization from absolute ethanol yields 5.4 g of the title compound, melting point 266°-268° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[O:22]1.CN(C)C=O>[Pd].O>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=3)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:24][C:23]=2[O:22]1
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)OCO3)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
In a flask was placed tert-butyl 5-bromonicotinate (1.00 g, 3.87 mmol), 10% w/w palladium on carbon (210 mg, ˜0.2 mmol Pd), potassium carbonate (1.10 g, 7.96 mmol), 3,4-methylenedioxy-phenyl boronic acid (0.96 g, 5.79 mmol), dimethylformamide (50 mL) and water (250 L). The flask was purged with nitrogen and then heated, with stirring, to 90° C. for 15 hr. The reaction mixture was allowed to cool, diluted with water (350 mL) and extracted with CH2Cl2 (4X). The combined extracts was washed with water, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica (gradient, CH2Cl2 to 50% ether/CH2Cl2) to provide an off-white solid (1.02 g, 88%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]3[CH:25]=[CH:26][C:27](Br)=[CH:28][C:18]=3[N:17]=2)[N:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1.[C:46]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:46])=[CH:12][C:11]=2[C:16]2[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]3[CH:25]=[CH:26][C:27]([C:38]4[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=4)=[CH:28][C:18]=3[N:17]=2)[N:6]=1)=[O:4]
Reactant: CNC(=O)c1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)no1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2ccc(C)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 80 °C
Yield: 11.9 %

Procedure:
To a solution of 3-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-[1,2,4]oxadiazole-5-carboxylic acid methylamide (150 mg, 0.32 mmol) in DMF (2 mL) in a sealed vessel are added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (85 mg, 0.38 mmol), 2 M Na2CO3 solution (0.48 mL, 0.96 mmol) and PdCl2(PPh3)2 (11 mg, 0.02 mmol) at room temperature. The solution is heated to 80° C. for 2 hours. The reaction mixture is cooled to room temperature and filtered through diatomaceous earth and concentrated in vacuo. Purification via flash chromatography (10 g silica gel, 2-3.5% MeOH/CH2Cl2) affords the title compound (18.4 mg, 12%). LCMS (ESMS): m/z 469.30 (M++1)
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4.[CH3:33][NH2:34]>O1CCCC1>[CH2:20]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[N:7]3[C:29](=[O:30])[N:4]([CH2:3][CH2:2][NH:34][CH3:33])[C:5](=[O:32])[C:6]3([CH3:31])[CH2:18][C:17]2=1)[CH3:21]
Reactant: CN
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Solvent: C1CCOC1
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 29 using (3aSR,10RS)-2-(2-Bromoethyl)-6-ethoxy-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 22) and a 2 M solution of methyl amine in tetrahydrofurane instead of azetidine as starting materials. MS: m/z (MH+)=449.1
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:10][C:11](=[O:25])[C:12]([C:23]#[N:24])=[C:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)[CH3:9].C1C(C=O)=CC=C(Br)C=1>O1CCCC1.[Cu]I>[CH2:8]([O:10][C:11](=[O:25])[CH:12]([C:23]#[N:24])[C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:15][C:16]2([O:17][CH2:18][CH2:19][O:20]2)[CH2:21][CH2:22]1)[CH3:9]
Reactant: CCOC(=O)C(C#N)=C1CCC2(CC1)OCCO2
Reactant: [Li]c1ccccc1
Agent: [Cu]I
Agent: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: -30 °C
Reaction time: 2 h
Yield: 57.91 %

Procedure:
To a stirred suspension of CuI (5.67 g, 29.88 mmol) in tetrahydrofuran (70 mL) was added phenyl lithium (1.8M dibutyl ether) (33.2 mL, 59.76 mmol) at −78° C. and the resulting mixture was allowed to stir at −30° C. for 2 h. To the resulting reaction mixture at −78° c. was added the pre-cooled solution of cyano-(1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester (262) in tetrahydrofuran (30 mL) and the resulting mixture was allowed to stir at −30° C. for 1 h. The reaction was monitored by silica TLC (P-anisaldehyde active). The reaction mixture was quenched with saturated NH4Cl-solution and the reaction mixture was diluted with ethyl acetate and the organic layer was separated. The organic part was dried over Na2SO4 and concentrated under reduced pressure, The resulting crude product was purified over silica gel (normal, 100-200 mesh) column chromatography using a gradient eluent 2% to 10% ethyl acetate in hexane to get cyano-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester (263) (3.8 g, 57.91%), as colorless gummy liquid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].C1O[C:18]2C=CC=C[C:17]=2[O:16]1.CC(C(OC(=O)C)OC(=O)C)=C>>[C:17]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:16])[CH3:18]
Reactant: c1ccc2c(c1)OCO2
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Agent: C=C(C)C(OC(C)=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (A) comprises the steps of (1) reacting 1,2-methylenedioxybenzene and 2-methyl-3,3-diacetoxypropene with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and (2) subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification, to thereby adjust a content of 1-acetyl-3,4-methylenedioxybenzene as a by-product in the 2-methyl-3-(3,4-methylenedioxyphenyl)propanal to from 50 to 3000 ppm.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 52 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (53 mg, 0.095 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.14 mL, 0.14 mmol). The mixture was heated in a microwave reactor at 120° C. for 500 seconds and 1 N hydrochloric acid (0.14 mL, 0.14 mmol) was added. The mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with brine and concentrated. The solid was washed with ether and dried overnight under a nitrogen stream at 45° C. to afford 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (27 mg, 52%). 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.97 (m, 1H), 2.44-2.33 (m, 4H), 2.14-2.04 (m, 1H), 1.99-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4: 546.0982 (M+H)+, found: 546.0982 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:13]=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:18][N:17]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1c(Cl)c2ccc(Br)cc2[nH]c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2c2[nH]ncc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of 7-bromo-4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (8.0 g, 27.9 mmol) in 150 mL of DMF at 80° C. is added hydrazine hydrate (2 mL, 33.5 mmol) at 80° C. The reaction medium is stirred for 24 hours at 80° C. and then cooled to room temperature and filtered. The solid obtained is washed with diisopropyl ether and dried to give 5.3 g of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a pale yellow powder (yield: 72%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]([OH:17])=[O:16])(=[O:4])=[O:3].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:2]([C:5]2[C:6]3[C:11](=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:4])=[O:3])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
5-Chlorosulfonyl-naphthalene-1-carboxylic acid 45 (2.00 g, 7.39 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (2.24 g, 3.1 mL, 22.2 mmol) was added followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 8.13 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 46 (3.0 g, 93%) as a yellow foam. 1H NMR (300 MHz, d6-DMSO) δ 9.11 (d, 1H), 8.62 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.62 (m, 2H), 3.91 (d, 1H), 3.62 (m, 2H), 3.15 (m, 1H), 2.67 (m, 2H), 1.89 (m, 2H), 1.52 (m, 2H), 1.40 (s, 9H); LC/MS m/z 435 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([NH2:13])=[O:12])C.CCOCC.[OH-].[Na+]>C(O)(=O)C>[C:11]1(=[O:12])[NH:13][CH:4]=[CH:5][N:6]2[CH:10]=[CH:9][CH:8]=[C:7]12
Reactant: CCOC(Cn1cccc1C(N)=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1[nH]ccn2cccc12
Yield: 80 %

Procedure:
1-(2,2-diethoxyethyl)pyrrole-2-carboxamide (3.0 g, 13.2 mmol) was dissolved in glacial acetic acid. The reaction mixture was allowed to reflux and the reaction was continued by thin layer chromatography in a 100% ether system. At the end of the reaction, the reaction mixture was made basic with a 2N solution of sodium hydroxide. The reaction mixture was then extracted with ethyl acetate, washed with a saturated sodium bicarbonate solution, dried over MgSO4 and evaporated. The product was purified by recrystallization in CH2Cl2 -hexane to give the title compound, pyrrolo[1,2-a]pyrazin-1(2H)-one (80%), m.p. 227°-228° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:20][S:21]([O:10][C:6]1[C:5]([O:11][CH3:12])=[CH:4][CH:3]=[C:2]([Br:1])[C:7]=1[CH:8]=[O:9])(=[O:23])=[O:22].[Br:1][C:2]1[C:7]2[CH:8]=[CH:20][S:21](=[O:23])(=[O:22])[O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(C=O)c1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)c(C=O)c1OS(C)(=O)=O
Product: COc1ccc(Br)c2c1OS(=O)(=O)C=C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %
Yield: 22 %

Procedure:
To a stirred solution of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (0.33 g, 1.43 mmol) and triethylamine (0.17 g, 1.71 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.19 g, 2.3 mmol) at 0° C., the reaction was stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes, by which time a brown colour had developed. Water (20 mL) was added, the mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with brine, dried over MgSO4, filtered and evaporated to give a crude solid (0.42 g). Flash chromatography over silica gel (60 g), eluting with hexane-ethyl acetate (3:1), gave 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate (320 mg, 72%) and 5-bromo-8-methoxybenzo[e][1,2]oxathiine 2,2-dioxide (90 mg, 22%) as white solids. The 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate had m.p. 95-97° C.; NMR Spectrum δH (300 MHz, CDCl3) 10.30 (1H, s, CHO), 7.58 (1H, d, J 8.9 Hz, 4-H), 7.11 (1H, d, J 8.9 Hz, 5-H), 3.95 (3H, s, OCH3), 3.57 (3H, s, SCH3); NMR Spectrum δC (75 MHz, CDCl3) 40.4, 57.1, 115.5, 118.3, 129.2, 133.2, 138.9, 152.9, 190.0; νmax/cm−1 (thin film) 1705, 1565, 1468, 1399, 1363, 1293, 1219, 1165, 1130, 971, 878, 800; m/z (ES) 374/372 (MNa2H2O+, 100%), 333/331 (MNa+, 80); Rf (hexane-ethyl acetate 1:1) 0.35. The 5-bromo-8-methoxybenzo[e][1,2]oxathiine 2,2-dioxide had m.p. 186-188° C.; Elemental Analysis Found: C, 37.3; H, 2.2; S, 10.9; Br, 27.2 (C9H7BrO4S requires C, 37.13; H, 2.42; S, 11.01; Br, 27.45%); NMR Spectrum δH (300 MHz, CDCl3) 7.62 (1H, d, J 10.5 Hz, 4-H), 7.47 (1H, d, J 10.5 Hz, 6-H), 6.96 (1H, d, J 10.5 Hz, 7-H), 6.88 (1H, d, J 10.5 Hz, 3-H), 3.88 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 57.0, 113.7, 116.2, 120.3; 123.9, 129.9, 135.8, 142.0, 149.1; νmax/cm−1 (nujol mull) 3091, 2959, 2924, 2854, 1608, 1569, 1468, 1367, 1309, 1270, 1169, 1080, 909; Rf(hexane-ethyl acetate 1:1) 0.60.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Yield: 36.7 %

Procedure:
Benzyl alcohol (28 mL, 270 mmol) and triethylamine (3.8 mL, 27 mmol) were combined and stirred over an ice bath, under nitrogen (N2). 4-Bromobutyryl chloride (1) (3.1 mL, 27 mmol) was added in a dropwise fashion, then the reaction was stirred an additional 30 minutes. The completed reaction was poured into 250 mL H2O and extracted with Et2O (3×200 mL). The ether extracts were combined, dried over MgSO4, and solvent removed in vacuo. Resulting crude product was purified by column chromatography, eluting with EtOAc/Hex (10/90) to afford 2.55 g (37%) of the desired benzyl 4-bromobutyrate (2a). 1H NMR (200 MHz, CDCl3) d 7.4 (s, 5H), 5.2 (s, 2H), 3.4 (t, 2H), 2.6 (t, 2H), 2.2 (p, 2H); mass spec (DCl, NH3) (M+NH4)+ 275.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[C-:18]#[N:19].[Na+].O>CN(C)C=O>[C:18]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:10])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)#[N:19]
Reactant: [C-]#N
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 63.4 %

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (1.09 g) and sodium cyanide (0.6 g) in dimethylformamide (30 ml) were heated at 65°-70° C. for 1 hour. The reaction mixture was then cooled, poured into water (150 ml), and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous brine, dried (Na2SO4) and evaporated to dryness to give a pale yellow solid (0.76 g) which was triturated with ether. The residual solid was recrystallised from ether/methanol to give the title compound 285 mg (24%), m.p. 217°-219° C. Found: C,48.3; H,3.4; N,18.4. Calculated for C12H10Cl2N4O: C,48.5; H,3.4; N,18.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=2[O-:11])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Br)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2cc([N+](=O)[O-])cc[n+]2[O-])CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a solution of 2-bromo-4-nitropyridine N-oxide (12 g), which is prepared according to the method disclosed in J. Org. Chem., 21, 1077 (1956), in ethanol (300 ml) are added 4-piperidinecarboxylic acid ethyl ester (22 g) and triethylamine (11.6 ml), and the mixture is stirred at 80° C. for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water, and the solvent is evaporated under reduced pressure to give the title compound (18 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])#[N:2].IC.[CH2:19](N(CC)CC)C>C(O)C.O>[C:1]([CH2:3][CH2:4][CH2:5][N:6]([CH3:19])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])#[N:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc(OC)c(NCCCC#N)c1
Solvent: CCO
Solvent: O
Solvent: CI
Product: COc1ccc(OC)c(N(C)CCCC#N)c1
Temperature: 50 °C
Yield: 52 %

Procedure:
To a stirred solution of N-(3-cyanopropyl)-2,5-dimethoxyaniline (46.2 g; 0.22 mol) in absolute ethanol (400 ml) were added iodomethane (47.7 g; 0.34 mol) and triethylamine (34.0 g; 0.34 mol). After stirring at 50° C. for 24 hours a further portion of iodomethane (47.7 g; 0.34 mol) was added to the reaction mixture, which was then heated at 50° C. for a further 24 hours. The reaction mixture was then cooled, diluted with water (500 ml) and extracted with dichloromethane (3×200 ml) and washed with water (2×400 ml). The resulting organic extract was dried (MgSO4), the solvent was then removed under reduced pressure to give a brown oil. The crude product was purified by flash chromatography, eluting first with hexane and subsequently increasing the polarity with dichloromethane. This procedure afforded the product as a colourless oil (26.8 g; 54%).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)#[CH:25]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(F)cc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3ccc(F)cc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-fluorobenzene. MS (+ESI) m/z: 391.1.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[Si:3]([O:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH2:19][C:20]([O:22][CH3:23])=[O:21])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.35 g, 8.7 mmol) was added to a solution of 3-((t-butyldimethylsilyl)oxy)phenol (0.49 g, 2.2 mmol), methyl 2-bromoacetate (0.37 g, 2.4 mmol), and dimethylformamide (2 mL) in a 50 mL round bottom flask under a nitrogen atmosphere at room temperature. The solution was heated in a 50° C. oil bath and allowed to stir overnight for approximately 16 hours. The resulting mixture was cooled to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 0.5 g (77%) of methyl 2-(3-((t-butyldimethylsilyl)oxy)phenoxy)acetate.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[O:16]([CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:25][CH2:26]1
Reactant: c1ccc(OCC2CCNCC2)cc1
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)cccc1[N+](=O)[O-]

Procedure:
A mixture of 40.0 g. 1-(2-amino-3-nitrophenoxy)-2,3-epoxypropane, 36.2 g. 4-phenoxymethylpiperidine and 450 ml. ethanol is stirred for 18 hours at ambient temperature and the solution thereby obtained of 2-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-3-nitrobenzene (m.p. 117°-118° C.) is subsequently hydrogenated at ambient temperature in the presence of 1.0 g. platinum oxide. After filtration, the filtrate obtained is acidified with dilute hydrochloric acid, evaporated and the evaporation residue redissolved in ethanol/ethyl acetate. There are obtained 72.3 g. 2,3-diamino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzene trihydrochloride (81% of theory) in the form of an amorphous substance.