Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[C:8]([F:15])=[C:7]2[F:16])[CH3:2].[CH2:17]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26](O)[C:27]#[CH:28])[CH2:22][CH2:21]1)[CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11]([CH:10]=[C:9]([O:14][CH:17]([CH:20]3[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[C:18]#[CH:19])[C:8]([F:15])=[C:7]2[F:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1ccc2cc(O)c(F)c(F)c2c1
Reactant: C#CC(O)C1CCC(CCC)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(Oc1cc2ccc(OCC)cc2c(F)c1F)C1CCC(CCC)CC1
Reaction time: 18 h

Procedure:
10.5 g (46.8 mmol) of 6-ethoxy-3,4-difluoronaphthalen-2-ol are initially introduced in 100 ml of THF together with 10.0 g (55.5 mmol) of 1-(4-propylcyclohexyl)prop-2-yn-1-ol and 15.0 g (57.2 mmol) of triphenylphosphine, and 11.5 ml (59.1 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1). The further purification is carried out by recrystallisation from n-heptane, giving 7-ethoxy-1,2-difluoro-3-[1-(4-propylcyclohexyl)prop-2-ynyloxy]naphthalene as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CNc1nc(Cl)ncc1N
Temperature: 60 °C
Yield: 69.4 %

Procedure:
To a stirred solution of 2-chloro-N-methyl-5-nitropyrimidin-4-amine (1.9 g, 10 mmol) in acetic acid (30 mL) was added iron powder (4 g, 71 mmol), and the suspension mixture was heated to 60° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was diluted by brine and ethyl acetate. The solid was filtered off, and the filtrate was extracted with ethyl acetate (50 mL*12). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated to give the title compound (1.1 g, 69%). MS (ES+) C5H7ClN4 requires: 159, 161. Found: 160, 162 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(O[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[C:18]#[N:19])C>C(O)C>[C:20]([C:17]1[CH:16]=[N:12][N:11]([C:3]2[C:2]([Cl:1])=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][N:5]3[N:4]=2)[C:18]=1[NH2:19])(=[O:22])[CH3:21]
Reactant: CCOC=C(C#N)C(C)=O
Reactant: NNc1nn2c(c1Cl)CCCC2
Solvent: CCO
Product: CC(=O)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
0.56 g (3 mmol) 3-Chloro-2-hydrazino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine was dissolved in 5 ml ethanol and treated with 0.42 g (3 mmol) 2-ethoxymethylen-3-oxobutyronitrile. After heating under reflux for 3 hours, the mixture was concentrated and the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:18][CH2:17][CH2:16][N:15]([CH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:10]=[N:11][CH:12]=1)[CH3:26]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cncn1-c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)Cc1cncn1-c1ccc(C#N)cc1
Yield: 39 %

Procedure:
A solution of tert-butyl N-[2-([[1-(4-cyanophenyl)-1H-imidazol-5-yl]methyl](methyl)amino)ethyl]carbamate (90 mg, 0.25 mmol, 1.00 equiv) in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions (waters-1): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, Phase A: water with 0.03% NH4OH Phase B: water with 0.05% TFA; Gradient B (20%˜50% 2 min˜100% 11 min); Detector, UV 254 nm to afford 25.4 mg (39%) of 4-(5-(((2-aminoethyl)(methyl)amino)methyl)-1H-imidazol-1-yl)benzonitrile trifluoroacetate as a white solid. 1H-NMR (300 MHz, CD3OD): δ 7.98-7.95 (m, 3H), 7.83-7.80 (m, 2H), 7.15 (s, 1H), 3.60 (s, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.50 (t, J=6.3 Hz, 2H), 2.16 (s, 3H) ppm. LCMS (method S, ESI): RT=1.18 min, m/z=256.3 [M+H]+.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.CON(C)[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:24].CC#N.C(=O)=O>C1COCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:24]
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1ccnnc1
Agent: CC[Si](Cl)(CC)CC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1ccnc1C(=O)c1ccnnc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6 M in hexane, 3.65 mL, 5.84 mmol) was added to a solution of 1-methylimidazole (0.452 mL, 5.7 mmol) in THF (30 mL) at −78° C. The mixture was stirred at −78° C. for 15 min. Chlorotriethylsilane (0.955 mL, 5.7 mmol) was added slowly. The mixture was removed from the dry ice/acetone bath and was stirred for 30 min. The mixture was again cooled in a dry ice/acetone bath before addition of a second portion of n-BuLi (1.6 M in hexane, 3.65 mL, 5.84 mmol). The mixture was stirred at −78° C. for 1 hour, then transferred to an ice bath and stirred 10 min. The mixture was again cooled in a dry ice/acetone bath before addition of a solution of N-methoxy-N-methylpyridazine-4-carboxamide (793 mg, 4.74 mmol, Intermediate 29, step a) in THF (15 mL) via cannula. The reaction mixture was stirred at −78° C. for 30 min, then was transferred to a slurry of CH3CN/dry ice and stirred for 15 min. The reaction was quenched by addition of water (50 mL) and the mixture was extracted with EtOAc three times. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0-4% MeOH-DCM first column, 75-100% EtOAc-heptanes second column) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.Cl[C:21]([O:23][CH:24]([Cl:26])[CH3:25])=[O:22]>O1CCCC1>[OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:21]([O:23][CH:24]([Cl:26])[CH3:25])=[O:22])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: CC(Cl)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Yield: 57.1 %

Procedure:
A mixture of 5-hydroxy-12H-benzo[a]phenothiazine (5 g) and α-chloroethyl chloroformate (10 g) in tetrahydrofuran (20 ml) was refluxed for 9 hours, then the volatile components were evaporated away and the residue chromatographed on a column of silica gel, eluting with a 1:9 ethyl acetate-hexane mixture to afford the title compound (4 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH:6]1[CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH:6]1[CH2:10][C:9]2[NH:30][C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=3[C:8]=2[CH2:7]1)[CH3:5]
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 33.6 %

Procedure:
To 100 mg (0.32 mmol) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester in glacial acetic acid (3 mL), 63 mg (0.35 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was heated at 70° C. for about 5 hours. Until completion, the reaction was monitored by HPLC and TLC. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 1:1 followed by a trituration with Et2O yielded 45 mg (34%) of (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester as a light yellow solid, MS: 418 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36]COCC[Si](C)(C)C)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2cc(O)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12]1[CH:16]=[C:15]([CH:17]=O)[O:14][CH:13]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH2:17][C:15]2[O:14][CH:13]=[CH:12][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=Cc1ccco1
Reactant: Nc1cc(N)cc(C(=O)O)c1
Product: Nc1cc(NCc2ccco2)cc(C(=O)O)c1

Procedure:
This compound was prepared from 3,5-diaminobenzoic acid and 2-furfuraldehyde according to the procedure of Example 18.
Reaction SMILES: ClC1C=CC(C2(C3C=CC(Cl)=CC=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=CC=1>C(O)(=O)C.O>[OH:9][C:10]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:21]=2)=[O:19])[CH:14]=[CH:13][C:11]=1[OH:12]
Reactant: CCOC(=O)CCCn1cc(C(=O)Cc2ccc3c(c2)OC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)O3)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCn1cc(C(=O)Cc2ccc(O)c(O)c2)c2ccccc21
Yield: 76.3 %

Procedure:
Ethyl 4-(3-[(2,2-di[4-chlorophenyl]-1,3-benzodioxolan-5-yl)methylcarbonyl]indol-1-yl)butanoate (9.5 g) (see Preparation 9) was dissolved in acetic acid/water (9:1) (100 ml) and heated under reflux for one hour. The reaction mixture was cooled, evaporated to dryness and partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO4) and evaporated to a brown oil. Flash chromatography (silica, eluant=10:1 dichloromethane/ethanol) gave the title compound as a pale tan solid (4.5 g). LRMS m/z=382 (m+1)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Yield: 59 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoanisole, the hydrochloride salt of the title compound was formed in 59% yield as a white solid, mp 260-261 C. elemental Analysis for C28H29 NO2.HCl.0.4H2O: Calculated: C, 73.88; H, 6.82; N, 3.08 Found: C, 73.87; H, 6.70; N, 3.14
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:14]([CH2:13][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=2)[CH3:11])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CNc1ccc(Cl)cn1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1CN(C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.1 mmol) in tetrahydrofuran (4 ml) was added 5-chloro-N-methylpyridin-2-amine (128 mg, 1.14 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred for 30 min. The mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred at 80° C. for 8 hr. After cooling to room temperature, the mixture was added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 102 mg (33%) of the title compound:
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.[NH2:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([NH:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14])=[O:3])=[O:6])[CH3:9]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
5.13 ml (45.8 mmol) of ethyl isocyanatoacetate are added dropwise to a suspension of 10 g (45.8 mmol) of the compound (3.3) in 100 ml of tetrahydrofuran and the mixture is left to stir at room temperature for 3 h; the solvent is removed in vacuo and the residue is chromatographed through silica gel using ethyl acetate/methanol =20/1. 13.44 g (85%) of (3.4) are obtained as a pale yellow oil.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH:17]=[O:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH3:19][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.CCCCCCC>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH:17]([OH:18])[CH3:19])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: O=Cc1cc(Cn2cc([N+](=O)[O-])cn2)on1
Reactant: C[Al](C)C
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-isoxazole-3-carbaldehyde (666 mg, 3.00 mmol) in CH2Cl2 (22.0 mL) was treated at 0° C. with trimethylaluminum (15 mL of a 1M solution in heptane, 15.00 mmol). The reaction mixture was then stirred at 0° C. for 2 h. CH2Cl2 (100.0 mL) followed by sat. aq. NH4Cl (50 mL) was then added. The mixture was then treated with 1N HCl and the aq. layer was extracted with CH2Cl2 (20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a green oil. LC-MS-conditions 02: tR=0.72 min.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].C([N:7](CC)[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10](F)[C:9]=1O)C.[CH2:19]=[C:20]([C:24]([O-:26])=[O:25])[C:21]([O-:23])=[O:22].O>C1COCC1>[OH:22][CH:2]([CH3:3])[CH2:1][O:4][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]=[C:20]([C:24]([O-:26])=[O:25])[C:21]([O-:23])=[O:22]
Reactant: CCN(CC)c1ccc(F)c(F)c1O
Reactant: CC1CO1
Agent: C=C(C(=O)[O-])C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CONc1ccccc1
Temperature: 40 °C

Procedure:
2,9 mgr (0,06 mmol) of HNa at 60%, 161 mgr (1,26 mmol) of LiClO4 anhydrous and 51 ml (0,32 mmol) of propylene oxide are added to a solution of 100 mgr) 0,32 mmol) of the compound [4] in 0,33 ml of THF. The reaction mixture is heated at 40° C. for two days and then 2 ml of water are added. The aqueous layer is extracted with ACOEt, ethyl acetate, (2×5 ml). The combination of the organic layers is dried with MgSO4 and the solvent is eliminated thus obtaining 77 mgr (65%) of the desired product [5].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[CH:13][C:12]=2[CH:14]=1
Reactant: COc1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Compound 88 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, and the product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give the product as a solid: (0.025 g, 4.8%); MS 277 [M−H]−
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=C(C(O)=O)O[C:12]=1[Br:13].CN(C)C=O>ClCCl>[Br:7][C:8]1[CH:9]=[C:2]([C:1]([Cl:6])=[O:5])[O:3][C:12]=1[Br:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)c(Br)o1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (10.4 ml, 0.12 mol) was added to a suspension of 4,5-dibromo-2-furoic acid (27 g, 0.1 mol) in dichloromethane (300 ml) containing dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was re-dissolved in dichloromethane and concentrated in vacuo; this was repeated to give the title compound which was used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=1.C1C2C3C=CC=CC=3[O:21][C:20]=2[CH:19]=CC=1>>[C:20]([C:15]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1)(=[O:21])[CH3:19]
Reactant: COc1ccc2sc3ccccc3c2c1
Reactant: c1ccc2c(c1)oc1ccccc12
Product: COc1cc2c(cc1C(C)=O)sc1ccccc12
Yield: 55 %

Procedure:
The 2-methoxydibenzothiophene was subjected to a Friedel-Crafts acetylation as described for the corresponding dibenzofuran (as in Routier et al., supra) to give 55% of 3-acetyl-2-methoxy-dibenzothiophene, m.p. 163.4°-164.9° after recrystallization from a mixture of heptane and toluene. The PMR spectrum, 200 MHz, supported the structure.
Reaction SMILES: [P:1]([CH2:14][CH2:15][CH2:16][P:17]([CH2:24][CH2:25][CH2:26]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([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.[C:28]1([PH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([N-]C(C)C)(C)C.[Li+]>>[P:1]([CH2:14][CH2:15][CH2:16][P:17]([CH2:24][CH2:25][CH2:26][P:34]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([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
Reactant: c1ccc(PC2CCCCC2)cc1
Reactant: ClCCCP(CCCP(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)CCCP(c2ccccc2)C2CCCCC2)cc1

Procedure:
The procedure for the Synthesis of HexPh4P3Pr above was followed using (C6H5)2P(CH2)3P(C6H5)(CH2)3Cl (1.73 g, 4.15 mmol), Phenylcyclohexylphosphine (1.01 g, 6.81 mmol) and lithium diisopropylamide (4.4 ml, 8.8 mmol). Yield: 1.89 g (81.4%). 31P{1H} NMR (CDCl3, 122 MHz, δppm: —CH2P(Cyhex)Ph: −11.67 and −11.79; Ph2PCH2—: −16.52; —CH2P(Ph)CH2— −26.21 and 26.34 (>98% pure).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>>[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: BrCc1ccccc1Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccccc2Br)cc1

Procedure:
Analogously to Method D, 3.0 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 2-bromobenzyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.58 (1:1 EtOAc-heptane); Rt=6.36.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:14]=1)[NH2:11].Br[C:25]1[S:29][C:28]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:11][C:10]1[CH:12]=[C:13]([C:25]2[S:29][C:28]([C:30]3([OH:34])[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)[CH:14]=[C:8]([CH3:7])[CH:9]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: OC1(c2ncc(Br)s2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To 500 mL three-necked round bottom flask were added 2-methyl THF (720 mL) and an aqueous solution of sodium carbonate (2 M, 367 mL, 734 mmol). The solution was degassed for 30 min. The product of Step 1 (90 g, 367 mmol), Intermediate 1 (86 g, 367 mmol) and PdCl2(dppf) (8.05 g, 11 mmol) were added to the degassed solution under N2(g). The resulting mixture was stirred for 5 min at room temperature and was then heated to 80° C. After ca. 9 hours, the heating mantle was removed and the reaction was cooled to 30° C. The reaction mixture was filtered through a pad of SolkAFloc employing water (500 mL) and ethyl acetate (500 mL) to complete the transfer. The filtrate was then transferred to a separatory funnel, using an additional 500 mL ethyl acetate and 250 mL brine to complete the transfer. The layers were cut, the organic washed with a mixture of water and brine (500 mL and 250 mL, respectively), and then the aqueous was back extracted with ethyl acetate (400 mL). The organics were combined, dried over MgSO4 (100 g), filtered, and concentrated in vacuo to yield a brown crystalline solid. This material was recrystallized from hot ethyl acetate (250 mL at 60° C.), using hexanes as a counter-solvent (750 mL) to yield 1-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol (88 g, 338 mmol, 92%). MS APCI: [M+H]+ m/z 261.2. 1H NMR (500 MHz, DMSO-D6) δ 7.87 (s, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.45 (s, 1H), 6.34 (s, 1H), 5.14 (s, 2H), 2.52-2.48 (m, 2H), 2.31 (q, J=9.3, 2H), 2.17 (s, 3H), 1.93-1.80 (m, 2H).