Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:17]=2[NH:16][CH:15]=[C:14]3[C:18](=[O:22])[C:19]([O-])=[O:20])=[CH:5][CH:4]=1.[K+].[C:24]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:24]([N:32]1[CH2:37][CH2:36][N:35]([C:19](=[O:20])[C:18]([C:14]2[C:13]3[C:17](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:10]=[CH:11][N:12]=3)[NH:16][CH:15]=2)=[O:22])[CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: COc1ccc(-c2ccnc3c(C(=O)C(=O)[O-])c[nH]c23)cc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccnc3c(C(=O)C(=O)N4CCN(C(=O)c5ccccc5)CC4)c[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure for the preparation of Examples 65-67 is the same as that described previously for the preparation of Precursor 5a and is as follows: Potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate, Precursor 4c (147 mg, 0.44 mmol), an appropriate 1-benzoylpiperazine derivative (0.44 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (101 mg, 0.44 mol) and Hunig's Base (0.5 mL) were combined in 5 mL of DMF. The mixture was stirred at rt for 8 h. DMF was removed via evaporation at reduced pressure and the residue was purified using a Shimadzu automated preparative HPLC System to give the corresponding 1-benzoyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetyl]-piperazine derivative.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][C:2]1=2.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(O)C.Cl>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH:9]=[CH:10][C:2]1=2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCCO2
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCCO2

Procedure:
The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843. (S)-tert-butyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) was stirred at +50° C. under argon for 16 hours. The reaction mixture was poured into 1M HCl (150 mL), the mixture was extracted with EtOAc (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash-chromatography on silica using EtOAc:Hexane (1:2) as eluent. Fractions containing product was combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1C[O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.C(Cl)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[CH:13][C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([C:35](=[O:36])[CH3:34])[CH2:29][CH2:28]5)=[N:24][N:25]=4)=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(Nc2nnc(-c3cnc(Nc4ccc5ncsc5c4)cc3NC(C)C)o2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 131) (40 mg, 0.08 mmol) in DCM (5 mL): THF (5 mL), added DIPEA (0.08 mmol, 1.5 equiv.) and DMAP (0.008 mmol, 0.1 equiv.) and stirred for 5 min. Added acetyl chloride (0.8 mmol, 0.8 equiv.) dropwise at 0° C. Stirred the reaction mixture at 0° C. for 1 h, the reaction temperature was raised to room temperature and stirred overnight. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The DCM layer was collected, dried over Na2SO4, filtered and concentrated. The material obtained was purified by prep HPLC to afford the title compound, 1-(4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidin-1-yl)ethanone. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.57-1.66 (m, 2H), 1.97 (s, 3H), 2.00-2.06 (m, 2H), 3.77-3.82 (m, 1H), 3.93-3.98 (m, 1H), 4.03-4.06 (m, 2H), 6.17 (s, 1H), 7.53-7.56 (m, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.514 min; LCMS (ES-API), m/z 493.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.396 min; Purity: 99.4%.
Reaction SMILES: [C:1]1(C#C)C=CC=C[CH:2]=1.[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](Br)=[CH:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#C)(C)C>>[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:1]#[CH:2]
Reactant: Brc1ccccc1C#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: C#C[Si](C)(C)C
Product: C#Cc1ccccc1C#Cc1ccccc1

Procedure:
In an especially contemplated arm extension strategy depicted in FIG. 4, in which AD represents an adamantane or diamantane group. Phenylacetylene is a starting molecule that is reacted (A1) with TBA (supra) to yield tetrakis(mono-tolanyl)-adamantane. Alternatively, phenylacetylene can be converted (B1) to tolanylbromide that is subsequently reacted (C1) with trimethylsilylacetylene to form tolanylacetylene. TBA can then be reacted (A2) with tolanylacetylene to tetrakis(bistolanyl )-adamantane. In a further extension reaction, tolanylacetylene is reacted (B2) with 1-bromo-4-iodobenzene to bistolanylbromide that is further converted (C2) to bistolanylacetylene. The so formed bistolanylacetylene may then be reacted (A3) with TBA to yield tetrakis(tristolanyl)-adamantane.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH2:12].[CH3:13][O-:14].[Na+]>CO>[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14]
Reactant: Cn1ncc(CCN)c1N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(CCNC=O)c1N

Procedure:
To a solution of 2-(5-amino-1-methylpyrazol-4-yl)ethylamine dihydrochloride (2.98 g, 14 mmol) in methanol (50 ml) was added 28% sodium methoxide solution in methanol (5.4 ml, 28 mmol). The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. A mixture of the residue and ethyl formate (80 ml) was stirred under reflux for 16 hours. To the reaction mixture was added chloroform, and the mixture was filtered through Celite. The filtrate was concentrated in vacuo to give N-[2-(5-amino-1-methylpyrazol-4-yl)ethyl]formamide (2.7 g) as a brown oil. 1H-NMR(CDCl3) δ2.57 (2H, t, J=6.9 Hz), 3.40–3.44 (2H, m), 3.67(3H, s), 5.77 (1H, br), 7.15 (1H, s), 8.16 (1H, s)
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:34]2[CH:39]=[CH:38][C:37](O)=[C:36]([CH3:41])[CH:35]=2)([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][C:24]=1[CH3:42].C(OCC)(=O)C>ClCCl>[CH2:30]([C:29]([C:34]1[CH:39]=[CH:38][C:37]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:36]([CH3:41])[CH:35]=1)([C:26]1[CH:27]=[CH:28][C:23]([OH:22])=[C:24]([CH3:42])[CH:25]=1)[CH2:32][CH3:33])[CH3:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(O)c(C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Pyridine (3 mL, 37.2 mmol) and trifluoromethanesulfonic anhydride (5.7 mL, 34.7 mmol) were added to a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (9.0 g, 31.6 mmol) in dichloromethane (300 mL) at 0° C., and then the mixture was stirred at the same temperature for one hour. Ethyl acetate was added to the reaction mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=10/1 to ethyl acetate only) to give the title compound (4.9 g, 37%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.5 g, 1.84 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of tert-butyl (R)-piperidin-3-ylcarbamate (0.37 g, 1.84 mmol) in CH2Cl2 (5 mL), then triethylamine (0.51 μL, 3.68 mmol). The mixture was allowed to warm to room temperature and was stirred for 3 h. After quenching with water, it was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 5:1 CH2Cl2: hexanes gave tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 68%). LC/MS: m/z 435.5 (M+H)+ at 2.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[CH:25][C:24]=2[Br:34])=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[CH:25][C:24]=1[Br:34])[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1cc(Br)c(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)c(Br)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Boron trifluoride dimethyl sulfide (10 μL, 80 μmol) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(2-bromo-4-methoxy-5-isopropylphenoxy)benzoyl]glycine (1.0 mg, 2.0 μmol) and dichloromethane (0.50 mL). The reaction mixture was stirred at room temperature for 8 hours and then treated with ice-water, extracted with ethyl acetate and washed with water. The organic phase was dried over sodium sulphate and concentrated to give a light yellow solid. The solid was purified on column (MPLC, silica gel, chloroform/methanol/acetic acid, gradient elution from 1/0/0 to 95/5/0.5) to give 0.90 mg (94%) of N-[3,5-dichloro-4-(2-bromo-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 476.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1.[Cl-].[CH:33]([C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45]#[N:46])[CH:41]=2)[N:36]=1)=O.O1CCCC1.N12CCCN=C1CCCCC2>>[CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:33]/[C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:45]#[N:46])[CH:41]=4)[N:36]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1
Reactant: N#Cc1ccc2nc(C=O)ccc2c1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(/C=C/c3ccc4cc(C#N)ccc4n3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.222 g, 0.483 mmol) and 2-Formyl-quinoline-6-carbonitrile (80 mg, 0.4 mmol) in dry Tetrahydrofuran (6 mL, 80 mmol) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (66 uL, 0.44 mmol) (reaction mixture turns slightly yellow for a while and precipitation changes character) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. The mixture was rotovaped and the THF was evaporated off. The solid was dissolved in DCM and was chromatographed on silicagel (0-30% MeOH in EtOAc). Pure product 2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinoline-6-carbonitrile precipitates in one of the fractions (10): isolated by filtration. Yield: 6 mg white solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:5])[CH:11]=1)[C:15](=[O:17])[CH2:14][CH2:13]2
Reactant: O=C(O)CCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(Cl)cc(Cl)c21
Yield: 71.6 %

Procedure:
Thionyl chloride (45.2 g) was added dropwise at 40° C. to a solution of 3-(3,5-di-chlorophenyl)propionic acid (54.8 g) in methylene chloride (200 ml). After reaction was complete, excess thionyl chloride and the solvent were removed by distillation. The oily residue was added dropwise at 40° C. to a suspension of aluminium chloride (66.7 g) in methylene chloride (200 ml). The reaction mixture was added to dilute hydrochloric acid after 18 hours at 40° C. The aqueous phase was separated off and extracted once with methylene chloride (250 ml). The combined organic phases were freed from the solvent. The residue was recrystallized from cyclohexane. 36 g of a colorless solid (m.p.: 119-120° C.) were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[ClH:8].[CH3:9]O>>[ClH:8].[CH3:9][O:6][C:5](=[O:7])[C@H:2]([CH2:3][OH:4])[NH2:1]
Reactant: N[C@H](CO)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CO
Yield: 99 %

Procedure:
A solution of 47.7 mmol of D-serine in 476 ml of methanol was saturated with hydrochloric acid gas and allowed to react at room temperature for 2 hrs. Following the evaporation of the solvent, recrystallization with methanol and ether produced the object compound L-serine methyl ester hydrochloric acid salt (Yield: 99%, m.p.: 163-164° C., [α]25 D=−4.3(c 1.8, EtOH)). The structure of the synthesized compound was identified using FTIR, 1H-NMR and 13C-NMR.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 73.4 %

Procedure:
A solution of 45 mg (0.1 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 12 mg (0.12 mmol) of triethylamine and 12 mg (0.1 mmol) of pivaloyl chloride in 5 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction solution was diluted with 10 ml of methylene chloride, then washed with 5 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 4:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 39 mg (73% of theory) of tert-butyl (3RS,4RS)-4-[4-(2,2-dimethyl-propionyloxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 549 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]([O:13][Si](C)(C)C)=[CH:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[F:25]OC(F)(F)F>ClC(Cl)(Cl)F>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([F:25])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: FOC(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 108.8 %

Procedure:
A solution of 8.52 g of the aforesaid 7-chloro-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepine in 150 ml of trichlorofluoromethane was cooled to -70° C. and 2.4 g of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture then was warmed to room temperature and evaporated to dryness under reduced pressure to give 7.60 g of crude 7-chloro-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one as a light tan powder: mp 130°-140° C.; 19F NMR (CCl3D) δ-161.7 ppm (d,J=57 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Cl)[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCN(c4ccncc4)CC3)cc21
Temperature: 200 °C
Yield: 24.8 %

Procedure:
A mixture of 1-ethyl-7-chloro-4-quinolon-3-ylcarboxylic acid (182 mg) and 1-(4-pyridyl) piperazine (125 mg ) was heated to 200° C. for 20 minutes. The mixture was cooled and methanol (5 ml) was added. The resulting solid was filtered and washed with methanol (10 ml) to give the title compound (68 mg), as a solid: NMR (d6DMSO) δ 1.4(t,3H), 3.75°-3.85(m,4H), 3.9-4.0(m,4H), 4.55(q,2H), 6.9(d,1H), 7.2(d,2H), 7.3(dd,1H), 8.2(d,1H), 8.3(d,2H), 8.9(s,1H); m/e 379(M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH3:12].CO>C1COCC1>[CH3:1][C:2]1[C:6]([S:7]([NH2:12])(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: N
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(C)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3,5-Dimethylisoxazole-4-sulfonyl chloride (4.3 g; 21.8 mmol; 1 eq) is dissolved in THF (10 mL), ammonia in MeOH (55 mL; 2 M; 109 mmol; 5 eq) is added and the reaction is stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 100 mL of EtOAc. The organic phase is washed with a saturated aqueous solution of NH4Cl (100 mL) then dried over MgSO4. The solvent is removed under reduced pressure, affording 2.6 g (67%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.59 (s, 2H), 2.56 (s, 3H), 2.34 (s, 3H). HPLC (max plot) 96.5%; Rt 1.22 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-:8].[K+].[Br:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:14])=[O:13]>C(#N)C>[Br-:10].[C:12]([CH2:11][CH2:15][CH2:16][CH2:17][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:17][CH2:16][CH2:15][CH2:11][C:12]([OH:13])=[O:8])=[CH:4]1)([OH:14])=[O:13]
Reactant: CCCC(Br)C(=O)O
Reactant: [OH-]
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCCCn1c[n+](CCCCC(=O)O)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 2 equivalents of 2-bromopentanoic acid (2.66 g, 14.72 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and neutralized with 6M HBr. Volatiles were removed in vacuo and the resulting product will be collected and analyzed.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[C:7]([C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][C:12]([CH3:18])=[C:11]([CH3:19])[CH:10]=2)=[O:8].[N-]=[N+]=[N-]>C(O)C>[N:1]([C:16]1[C:15]([C:14]2[C:9]([C:7](=[O:8])[CH:6]=1)=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(N=[N+]=[N-])=CC2=O

Procedure:
An aqueous solution of sodium azide (4.4 g; 0.068 mole) was added at once to a refluxing suspension of 2-bromo-6,7-dimethyl naphtho-1,4-quinone (13.8 g; 0.052 mole) in ethanol (130 ml) and the resulting red solution refluxed for a further 2 mins. After cooling in ice the precipitated azide was separated, washed well with water and recrystallised from ethanol as an orange-red solid, m.p. 116°-119° C (d).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(CCl)cc1OCc1ccccc1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(C)nc(C)c2Cl)cc1OCc1ccccc1

Procedure:
In analogy to the method described in example A1, 6.11 g (38 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 10.5 g (40 mmol) of 3-benzyloxy-4-methoxybenzyl chloride and 1.52 g (38 mmol) of sodium hydride (60% suspension in liquid paraffin) are reacted in a total of 225 ml of N-methylpyrrolidone. After chromatography on silica gel (mobile phase: toluene/dioxane=10:1) and crystallization from petroleum ether, the title compound is isolated as a pale beige solid. Yield: 5.2 g (36% of theory). m.p.: 111-117° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][NH2:11]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: NN
Reactant: Nc1nc(Cl)cc(=O)[nH]1
Solvent: O
Product: NNc1cc(=O)[nH]c(N)n1
Yield: 45.4 %

Procedure:
A stirred suspension of 15.0 g (103 mmol) of 1 in 250 mL water was added 12 g (375 mmol) of anhydrous hydrazine, and the mixture was heated at reflux for 3 h. The resulting clear solution was cooled, and the precipitate which separated was collected by filtration, washed with water followed by ethanol and dried to give 6.6 g (46%) of white solid. mp decomposes at 313° C. (Literature mp 314-315° C., see Taylor, E. C; Cocuzza, J. A. Synthesis and Properties of 7-Azaxanthopterin. J. Org Chem. 1979, 44, 1125-1128.).