Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:23]([Cl:22])[CH:24]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(Cl)c(Cl)c2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (0.28 g), 3,4-dichlorophenethyl bromide (0.255 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichlorometbane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated inn vacuo to give an oil which was purified by column chromatograpby on silica eluting with dichloromethane containing hexane (30%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound, yield 0.233 g, m.p. 139°-142° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[NH:10][C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3].[H-].[Na+].[CH2:21](Br)[CH:22]=[C:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[N:10]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: CC(C)=CCBr
Reactant: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2CC=C(C)C
Yield: 64.6 %

Procedure:
81 Grams of 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 15 was dissolved in 500 ml of dimethylformamide, then 13 g of 60% oily sodium hydride and 50 g of prenyl bromide were added thereto and reacted similarly as in Example 17, after the reaction was finished, the reaction mixture was treated similarly, there was obtained yellow oily product. This oily product was subjected to treatment by means of a silica gel flush column chromatography by using a mixed solvent of methylene chloride-methanol (100:1) as the eluent. The secondary eluted portion was collected and concentrated, there was obtained 67 g (64.6%) of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone as pale yellow oily product. This oily product become a solid matter then it was allowed to stand at below 20° C., the solid matter was washed with ice-cooled petroleum ether to change white solid, dried in a desiccator and pulverized, there was isolated white powdery product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:31]([C:33]([OH:38])([CH2:36][CH3:37])[C:34]#[CH:35])[CH3:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]([CH2:36][CH3:37])([OH:38])[CH2:34][CH3:35])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: C#CC(O)(CC)CC
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Product: CCC(O)(C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1)CC

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (82) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 3-ethylpent-1-yn-3-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.30 (m, 2H), 5.17 (s, 1H), 2.59 (s, 3H), 1.69 (m, 4H), 1.01 (m, 6H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.64.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9](=[CH:12]N(C)C)[CH:10]=O)[CH:6]=[CH:7][CH:8]=1.[OH:18][CH:19]([CH2:23][CH3:24])[CH2:20][NH:21][NH2:22]>C1C=CC=CC=1>[OH:18][CH:19]([CH2:23][CH3:24])[CH2:20][N:21]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH:12]=[N:22]1
Reactant: CCC(O)CNN
Reactant: CN(C)C=C(C=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CCC(O)Cn1cc(-c2cccc(C(F)(F)F)c2)cn1

Procedure:
A mixture of 10 g. of 2-(m-trifluoromethylphenyl)-3-dimethylaminoacrolein, 5 g. of 2-hydroxybutylhydrazine and 100 ml. of benzene is refluxed for 2.5 hours. The benzene is evaporated off, ether added, and the reaction mixture cooled to obtain a precipitate which is recovered by filtering, washed with pentane, dissolved in methylene chloride, dried, treated with charcoal and filtered. The resulting solution is treated by addition of pentane and the resulting precipitate recovered by filtering, washed with pentane and dried under reduced pressure to obtain 1-(2-hydroxybutyl)-4-(m-trifluoromethylphenyl)-pyrazole, m.p. 77°-79°C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCOCc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOCc1cc([N+](=O)[O-])c(F)cc1Br

Procedure:
By the method of Example 2, Step D, 7.18 g (0.0308 mole) of ethyl 2-bromo-4-fluoro benzyl ether, 2 ml of fuming nitric acid, and 18 ml of concentrated sulfuric acid were reacted in 20 ml of 1,2-dichloroethane, yielding 3.1 g of ethyl 2-bromo-4-fluoro-5-nitrobenzyl ether.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3 solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([OH:19])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][O:23][CH3:24]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Agent: Cl
Product: CON(C)C(=O)CC1c2ccccc2CCc2ccccc21

Procedure:
In analogy to example 55, step 1, from 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (CAS RN: [4037-50-7]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a colorless oil, MS (ESI+): m/z=296.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])(=[O:12])=[O:11])[CH3:2].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])(=[O:12])=[O:11])[C:37](=[O:38])[CH2:36][N:27]1[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 95.1 %

Procedure:
The title compound (2.69 g, 95%) was synthesized by the reaction of N-[2-(2-Nitro-4-trifluoromethyl-benzenesulfonylamino)-ethyl]-glycine ethyl ester (2.00 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.55H), 11.28 (s, 0.45H), 8.57 (s, 0.55H), 8.54 (s, 0.45H), 8.50 (t, 0.55H), 8.38 (t, 0.45H), 8.29˜8.18 (m, 2H), 7.31 (s, 0.55H), 7.22 (s, 0.45H), 4.64 (s, 1.1H), 4.46 (s, 0.9H), 4.21 (s, 0.9H), 4.16 (q. 0.9H), 4.07 (q. 1.1H), 3.95 (s, 1.1H), 3.49 (t, 1.1H), 3.37 (q, 1.1H), 3.25 (t, 0.9H), 3.09 (t, 0.9H), 1.75 (s, 3H), 1.23 (t, 1.35H), 1.18 (t, 1.65H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].FC(F)(F)C(O)=O.[H][H]>[Pd].S([O-])([O-])(=O)=O.[Ba+2].C(O)(C)(C)C>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCCC(C)CC=O

Procedure:
In a 3-L reaction flask were added 500.0 g (3.28 mol) of citral, 2.50 g (0.5 wt % based on the citral) of 5 wt. % Pd/barium sulfate, 10.0 g (22.9 mmol, 2.0 wt % based on the citral) of (2R,4R)-2-(bis-(4′-t-butylphenyl)methyl)-4-(ethylcarbamoyloxy)pyrrolidine, 2.6 g (22.9 mmol) of trifluoroacetic acid, and 500 mL of 10 wt % hydrous t-butanol in a nitrogen atmosphere. The resulting mixture was stirred and the atmosphere was exchanged with a hydrogen atmosphere (0.1 MPa (atmospheric pressure)). After stirring at 60° C. for 21 hours, the catalyst was filtered off and the residue was analyzed using gas chromatography. As a result, it was found that a conversion ratio from citral to citronellal was 99.4% and an optical purity was 90.9% e.e. The crude-citronellal thus obtained was distilled to obtain 398 g (2.58 mol, yield: 78.6%) of d-citronellal having a purity of 98%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[NH:3]1.[H][H]>[Pt]=O.C(O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[NH:3]1
Reactant: CN1C=NN(c2cccc([N+](=O)[O-])c2)N1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN1C=NN(c2cccc(N)c2)N1
Yield: 91.9 %

Procedure:
The nitro group was reduced as follows: To a 250 ml Parr bottle were added 800 mg (3.9 mmol) of 3-(1-methyltetrazol-3-yl)nitrobenzene, 200 mg platinum oxide, and 75 ml ethanol. The reaction was pressurized with 45 p.s.i. hydrogen for 1 hour, then catalyst removed by filtration, and the solvent evaporated to afford 635 mg (93.0%) of a white solid, mp 93°-95° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=[O:19]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:18]([C:9]2[S:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:11][CH:10]=2)[OH:19])[CH:20]=1
Reactant: c1ccc(-c2cccs2)nc1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: OC(c1ccc(-c2ccccn2)s1)c1cc(Br)ccc1Cl

Procedure:
2-(2-Pyridyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7-(1) to give 5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol as colorless powder. APCI-Mass m/Z 380/382 (M+H). (2) A solution of the above 5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol (3.52 g) in trifluoroacetic acid (45 ml) was added to a solution of sodium borohydride (1.75 g) in trifluoroacetic acid (45 ml), and the mixture was stirred at room temperature for 4 hours. Trifluoroacetic acid was evaporated under reduced pressure. The residue was basified with an aqueous potassium hydroxide solution, and extracted with diethyl ether. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to give 5-bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (2.42 g) as a colorless solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[C:8]([C:6]1[CH:7]=[C:2]([C:24]2[C:19]([O:18][CH3:17])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]=1[O:12][CH3:13])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ncccc1B(O)O
Reactant: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc([N+](=O)[O-])c(OC)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 81.8 %

Procedure:
step 1—A mixture of 5-bromo-1-tert-butyl-2-methoxy-3-nitrobenzene (0.48 g, 1.7 mmol; CASRN 474554-50-2), 37 (0.28 g, 1.8 mmol), Pd(PPh3)3 (0.19 g, 0.17 mmol) and Na2CO3 (0.53 g, 5.0 mmol) in DCM/MeOH (3:1, 8 mL) was subjected to microwave heating to 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.44 g (82%) of 3-(3-tert-butyl-4-methoxy-5-nitrophenyl)-2-methoxypyridine (98) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[Br:11][CH:12](Br)[CH3:13]>>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:13][CH2:12][Br:11])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1O
Reactant: CC(Br)Br
Product: C=CCc1ccccc1OCCBr
Yield: 17.9 %

Procedure:
Using the procedure described in Example I step A and starting from 43.5 g o-allylphenol and 140 g dibromoethane, 35 g of crude product are produced which after distillation under reduced pressure give 14 g of pure compound. The latter boils at 150°-154° under 18-20 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[Li]CCCC.[O:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:34]4([OH:37])[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)=[CH:7][CH:6]=3)[N:9]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: O=C1CCOCC1
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3ccccc23)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(C4(O)CCOCC4)cc3)cc3ccccc23)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A solution of the resulting 3-(4-bromophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline (0.61 g) in tetrahydrofuran (30 ml) was cooled to −78° C., followed by the dropwise addition of 1.6M n-BuLi (1.1 ml) in nitrogen atmosphere. Fifteen minutes later, a solution of tetrahydropyran-4-one (0.17 g) in tetrahydrofuran (1 ml) was added thereto, and the temperature of the reaction mixture was gradually raised to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale yellow oil (0.21 g, yield; 32.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[C:21]=1[O:22][CH3:23].[CH2:24](Br)[CH:25]=[CH2:26].C(=O)(O)[O-].[Na+]>O>[CH2:26]([N:9]1[CH2:10][CH2:11][C:12]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:21]([O:22][CH3:23])[C:7]=2[CH2:8]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1OC)CNCCc1cc(O)ccc1CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCN1CCc2cc(O)ccc2CCc2ccc(OC)c(OC)c2C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mg of 3,4-dimethoxy-10-hydroxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine, 42.6 ml of allyl bromide and 32.3 mg of sodium bicarbonate in 4 ml of dimethylformaide is stirred for 2 hours at 100°C in argon atmosphere. After cooling, 40 ml of water is added to the mixture, and the mixture is extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue is dissolved in benzene, passed through a column of 3.8 g of silica gel, and eluated with benzene - ethyl acetate (10 : 1). The evaporation of the solvent affords 106 mg of 6-allyl-3,4-dimethoxy-10-hydroxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine as a colorless oily material. IR: νmaxCHCl 3 3604, 3420 and 1641 cm-1.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:17])=[N:13][O:14][C:15]=1[CH3:16])=[O:10])[NH:2]2.[CH3:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1>>[CH3:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:25])[N:23]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3c(C)noc3C)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 3,5-dimethyl-isoxazole-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.35 min; [M+H]+=451.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[S:18]([CH3:21])(=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2′-methyl-2-(methylsulfonyl)biphenyl-4-carboxylate (270 mg; 0.89 mmol; 1 eq.) was dissolved in THF (5 mL) and MeOH (5 mL). sodium hydroxide (0.89 mL; 5 M; 4.44 mmol; 5 eq.) was added and the mixture was stirred at RT overnight. Solvents were evaporated and the crude mixture was partitioned between EtOAc and water. Aqueous phase was acidified with HCl 5N solution. The two phases were separated and the organic phase was washed with brine and dried over MgSO4. After filtration and evaporation of the solvents, the title compound was isolated as a beige solid (215 mg, 83%). 1H NMR (DMSO-d6, 300 MHz) δ 13.53 (br s, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.28 (dd, J=1.8, 8.0 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.42-7.23 (m, 4H), 2.90 (s, 3H), 2.02 (s, 3H). LC/MS (Method B): 289.2 (M−H)−. HPLC (max plot) 97.9%; Rt 3.83 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:10](C(=O)C(F)(F)F)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN1C(=O)C(F)(F)F
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 327 (16.0 mmol) in 1,4-dioxane (120 mL) was added LiOH.H2O (32.0 mmol, 2 equiv). The suspension was allowed to stir at room temperature for 16 h at which point TLC indicated complete consumption of starting material (KMnO4 stain for S.M.). The reaction was diluted with THF (120 mL), filtered through a glass frit and concentrated. The resulting syrup was diluted with THF/CHCl3 (1:1, 200 mL) and washed with saturated NaHCO3 (100 mL), brine (100 mL), dried (MgSO4), and purified via column chromatography (0–10% MeOH in CH2Cl2 with 0–1% NH4OH) to give [5-(S)-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (328) as a colorless foam. 1H NMR (400 MHz, CD3OD) δ=1.45 ppm (s, 9H), 1.47 (s, 9H), 1.69 (br s, 1H), 2.32–2.39 (m, 1H), 2.82 (dd, 1H, J=6, 13 Hz), 2.89 (dd, 1H, J=4, 13 Hz), 3.00 (dd, 1H, J=7, 11 Hz), 3.81 (dd, 1H, J=7, 11 Hz), 3.92–3.98 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ=26.0, 29.0, 29.1, 58.9, 67.8, 78.5, 79.1, 154.3, 155.7 pm.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[Cl:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:13]=1
Reactant: O=CC(Cl)C=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: CC(=O)O
Product: OCc1nc2ncc(Cl)cn2n1
Temperature: 80 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (28.5 g, 150 mmol, from step 6 of example A(1)) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product crystallized out as a white solid (25.5 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ 4.67 (s, 2 H), 5.62 (s, 1 H), 8.94 (d, J=2.45 Hz, 1 H), 9.81 (d, J=2.45 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([OH:6])[CH3:5].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.[H-].[Na+]>C1COCC1>[Cl:7][C:8]1[N:13]=[C:12]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:11]([Cl:15])=[CH:10][N:9]=1
Reactant: COC[C@H](C)O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1nc(Cl)ncc1Cl

Procedure:
(S)-1-Methoxypropan-2-ol (0.58 ml, 5.88 mmol) was added drop wise to a mixture of 2,4,5-trichloropyrimidine (0.63 ml, 5.34 mmol) and NaH (60% dispersion in mineral oil, 0.24 g, 5.88 mmol) in THF (10 ml) at room temperature. After 30 minutes the reaction mixture was partitioned between water and DCM, the organic layer washed with water, dried over Na2SO4 and evaporated to give the title compound as a yellow-brown oil. (UPLC-MS 7) tR 1.01; ESI-MS 237.0 and 238.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC(C)C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Methyl 3-hydroxybenzoate (1 eq.) and 2-bromopropane (2 eq.) were dissolved in DMF. Subsequent to addition of potassium carbonate (2 eq.), the resulting mixture was stirred at 100° C. for 24 hours. The mixture was charged into water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby the title compound was obtained (yield: 49%).