Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][C:8]=1[CH3:18])[CH3:2].[N:20]1[N:21]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[OH:36])[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][O:36][C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[N:21]2[N:22]=[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[N:20]2)=[CH:9][C:8]=1[CH3:18])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCCCBr)cc1C
Reactant: Oc1ccc(Cl)cc1-n1nc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
To a mixture of [4-(3-bromo-propylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (139 mg, 0.4 mmol) and 2-benzotriazole-2-yl-4-chloro-phenol (108 mg, 0.44 mmol) in MeCN (3 mL) was added Cs2CO3 (156 mg, 0.48 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was filtrated through Celite and washed with ethyl acetate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to give 145 mg of the desired ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH3:16].CN([CH:20]=[O:21])C>[OH-].[Na+]>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][N:11]2[CH3:16]
Reactant: CN(C)C=O
Reactant: Cn1ccc2c(F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2c(F)cccc21
Temperature: 0 °C
Yield: 55 %

Procedure:
Under stirring at 0° C., phosphoryl chloride (2.07 ml, 22.1 mmol) was added dropwise to DMF (30 ml). After completion of the dropwise addition, a solution of 4-fluoro-1-methylindole (2.20 g, 14.7 mmol) in DMF (15 ml) was added dropwise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured in 1N NaOH (120 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, 4-fluoro-1-methylindole-3-carbaldehyde (1.43 g, 55%) was obtained as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>CN(C)C=O>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Clc1ccc(CCCBr)cc1
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CCCc1ccc(Cl)cc1)CC2
Yield: 37 %

Procedure:
Prepared from 3-(4-chlorophenyl)propyl bromide and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in anhydrous dimethylformamide. Yield: 37% of theory, Melting point: 153° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH3:18].[Cl:19]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:18])[Cl:19]
Reactant: CC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: ClCl
Agent: Cl
Solvent: CC(=O)O
Product: CC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, and using as the reactants (1-oxo-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (2.89 g., 0.01 mole), glacial acetic acid (50 ml.), chlorine (710 mg., 0.01 mole) and concentrated hydrochloric acid (1 drop) there is obtained (1-oxo-2-methyl-2,6,7-trichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.S(Cl)([Cl:16])=O>>[CH3:1][C:2]1([C:11]([Cl:16])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)Cc2ccccc2C1
Product: CC1(C(=O)Cl)Cc2ccccc2C1

Procedure:
A stirred mixture of 2,3-dihydro-2-methyl-1H-indene-2-carboxylic acid (6.70 g) and thionyl chloride (70 ml) is heated under reflux for 14 hr. The ecess of thionyl chloride is removed and the acid chloride is distilled. Yield 5.35 g, 72%, bp. 93°-98° C./3 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:36][NH2:37]>C(O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11](=[N:36][NH2:37])[NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=S)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(C(=NN)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-piperidin-1-yl-thiobenzamide (unpurified product of the previous step: F67-03), ethanol (5 mL), hydrazine monohydrate (0.5 mL) was placed in a test tube and heated for 1.5 hours under reflux. After completing the reaction, the reaction mixture was concentrated under reduced pressure while adding toluene several times. The residue thus obtained was subjected to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc(-c2ccc(F)cc2)no1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1cc(-c2ccc(F)cc2)no1
Yield: 97 %

Procedure:
A mixture of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (27.14 g, 80.70 mmol), hydrazine hydrate (9.8 mL, 202 mmol), and ethanol (700 mL) was heated at reflux under nitrogen for two hours. The reaction mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in ethyl acetate, and the solution was washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 16.14 g of 2-[3-(4-fluorophenyl)isoxazol-5-yl]ethylamine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[Si:41](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N1C=CN=C1>CN(C=O)C>[Si:41]([O:40][C@@H:12]1[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5′-O-Dimethoxytritylthymidine is silylated with 1 equivalent of t-butyldiphenylsilyl chloride (TBDPSCl) and 2 equivalents of imidazole in DMF solvent at room temperature. The 5′-protecting group is removed by treating with 3% dichloracetic acid in CH2Cl2.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]3[C:17]([C:33]#[N:34])=[C:18]([NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[S:19][C:13]=3[CH2:12]2)=[O:10])[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(C#N)(C)=O.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:33]#[N:34])=[C:18]([NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[S:19][C:13]=2[CH2:12]1)=[O:10]
Reactant: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCC1COC(C)(C)O1)C2
Agent: CC(=O)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCC(O)CO)C2
Yield: 80 %

Procedure:
0,26 mmol of 3-Cyano-2-[3-(2-methoxy-phenyl)-propanoylamino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (Example 30) are dissolved in 10 ml AcCN/H2O (2/1) and 0.1 eq PTSA is added. After stirring over night, some triethylamine is added and the solvent removed. Recrystallization from ethanol gives the desired product in 80% yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11]C)=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: COc1cc(C)c2c(c1C)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(C)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 4,7-dimethyl-5-methoxyindane (3.5 g) in dichloromethane (30 ml) was added a solution of boron tribromide (5.08 g) in dichloromethane (2 ml) at -78° C. The temperature was raised slowly to room temperature and the mixture was stirred at the same temperature for 1 hour. The mixture was extracted by addition of ice-water (10 ml) and ethyl acetate (50 ml). The organic layer was washed with aqueous sodum bicarbonate, water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to obtain 4,7-dimethyl-5-hydorxyindane (3.2 g) (Compound A-5). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[N:18]#[C:19]Br>O1CCCC1>[C:19]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)#[N:18]
Reactant: N#CBr
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC#N)C2
Temperature: 40 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.0 g, 4.34 mmol) was dissolved in tetrahydrofuran (120 ml), to which cyanogen bromide (2.76 g, 26 mmol) was added and the mixture was stirred at 40° C. for 4 hours. After completion of the reaction, the precipitated crystals were collected by filtration, and washed with water. As a result, 0.427 g of the title compound was obtained as yellow crystals (38.5%). Recrystallization from chloroform-methanol yielded the title compound as pale yellow needles (mp: 227°-230° C. (dec.)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:16][CH2:17][C:12]3([O:18][CH2:9][CH2:10][O:11]3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(N2CCC3(CC2)OCCO3)n1
Reaction time: 2.5 h

Procedure:
A solution of 18.5 g 2,4-dichloropyrimidine in 150 ml ethanol is added dropwise to a solution of 16 ml 4-piperidone-ethylene ketal and 17.5 ml triethylamine in 100 ml ethanol while cooling on ice. Subsequently the reaction mixture is stirred for a further 2.5 hours, the ethanol is then removed in a vacuum, the residue is admixed with 100 ml water and the aqueous mixture is extracted three times with 50 ml methylene chloride each time. After drying the combined organic phases over sodium sulfate and removing the solvent, the solid residue is recrystallized from ethyl acetate/isohexane. In this way 11 g 8-(2-chloro-pyrimidin-4-yl)-1,4-dioxa-8-aza-spiro[4.5]decane is obtained as a white powder. f.p.: 135-137° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:19][CH2:11][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)c1cccc(CBr)c1

Procedure:
Methyl m-toluate was brominated with NBS and AIBN as described in Example 21 to give methyl m-bromomethylbenzoate, and this was further reacted with triethyl phosphite as described in Example 2 without further purification.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=3[F:34])[C:23]([NH:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])=[O:24])([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=3[F:34])[C:23]([NH:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])=[O:24])([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2
Reactant: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(NC(=O)c3ccccc3)O[C@H]3C[C@H]32)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(N)O[C@H]3C[C@H]32)c1
Temperature: 65 °C
Yield: 19.1 %

Procedure:
A flask was charged with 3-((1S,5R,6S)-3-benzamido-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoro-N—((S)-1-methoxypropan-2-yl)benzamide (0.3780 g, 0.795 mmol), 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.143 ml, 0.954 mmol) and MeOH (7.95 ml). The reaction mixture was heated to 65° C. for 4 hours. The crude product was adsorbed onto a plug of silica gel and purified by flash chromatography, eluting with a gradient of 10% to 100% EtOAc:EtOH (75:25) in hexane, to provide the title compound (0.0563 g, 0.152 mmol, 19.07% yield).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30]([N:32](CC)[CH2:33]C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[CH3:30][N:32]([CH3:33])[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccc(COCCO)cc2)cc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
3-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one (85 mg, 0.215 mmol) was mixed with triethylamine (0.09 mL, 0.644 mmol) in DCM (3 mL). The mixture was cooled in ice-water bath. Methane sulfonylchloride (3.3 uL, 0.49 mmol) was added and the reaction mixture was allowed to warm to room temperature. The stirring was continued for further 2 hours. The reaction mixture was quenched with saturate NaHCO3 aqueous solution (3 mL). The aqueous phase was extracted with DCM (3×3 mL). The combined organic phase was dried over sodium sulfate and concentrated to give a brown oil which was mixed with dimethyl amine (4 mL, 6.44 mmol) in a screw cap vial and heated at 60˜70° C. for 3.5 hours. The reaction mixture was concentrated, redissolved in DCM (5 mL) and stirred with saturated NaHCO3 aqueous solution (3 mL). The aqueous phase was extracted with DCM (3×4 mL). The combined organic phases were dried over sodium sulfate and concentrated to give a pale brown oil, which was purified on silica gel eluting with DCM containing 1˜2.5% 2M ammonia in methanol to give the product as a white solid (74 mg, 82%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.56 (dd, 4H), 7.41 (d, 2H), 7.29 (d, 2H), 4.64 (s, 2H), 4.45 (s, 2H), 3.56 (t, 2H), 3.12 (s, 2H), 2.54 (t, 2H), 2.27 (s, 6H), 1.75 (m, 4H), 1.52 (m, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCCl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCN=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 4a (3.85 g, 7.71 mmol), sodium azide (2.51 g, 38.58 mmol) and nBu4NI (5.7 g, 15.43 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 hrs. The solution was cooled to r.t. then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated under reduced pressure. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 4 (3.29 g, 85%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:37]=[CH:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:38]4[CH:37]=[CH:36][C:35]5[C:40](=[C:31]([Cl:30])[CH:32]=[CH:33][CH:34]=5)[N:39]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 8-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:18][OH:19])[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C2COC1CN(Cc1ccccc1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1C2COC1CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 41.2 %

Procedure:
A mixture of (rac)-3-benzyl-6-oxa-3-aza-bicyclo[3.2.1]octan-8-one (500 mg, 2.30 mmol), hydroxylamine hydrochloride (224 mg, 3.22 mmol) and pyridine (0.32 mL) in ethanol (5 mL) was heated to 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5 N Aqueous sodium hydroxide solution (10 mL) was added to the residue. The resulting solution was extracted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 5-10% ethyl acetate/hexane mixture as eluent to afford the title compound as a brown sticky liquid (220 mg, 43%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([Li])[N:3]=[CH:2]1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[O:1]1[C:5]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:4][N:3]=[CH:2]1
Reactant: [Li]c1cocn1
Reactant: C(=Nc1ccncc1)c1ccccn1
Product: c1ccc(C(Nc2ccncc2)c2cnco2)nc1

Procedure:
The title compound is prepared by reacting 4-oxazolyl lithium (obtained from 5-bromooxazole and butyl lithium) with 4-(2-pyridylmethyleneamino)pyridine in a manner similar to Examples 5, 6 and 7.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCCCC1)C(C)(C)CCC2(C)C
Yield: 93.9 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) and 760 mg (4.08 mmol) of 1-(2-chloroethyl)piperidine hydrochloride, 1.57 g (89%) of the expected compound was obtained in the form of a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([F:20])([F:19])[F:18])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:22]=3[O:29]C)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([F:20])([F:19])[F:18])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[OH:29])=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn(CC3CCCCC3)c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(CC3CCCCC3)c3c(C(F)(F)F)cccc23)c(O)c1
Yield: 72.6 %

Procedure:
Prepared according to Method D step C from 1-(cyclohexylmethyl)-3-(2,4-dimethoxy-phenyl)-7-(trifluoromethyl)-1H-indazole (0.841 g, 2.0 mmol), boron tribromide (1.14 mL, 12 mmol) and 0.5 mL of cyclohexene to give the product (0.567 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6])[CH:2]=[CH2:3].Cl.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:11][C:10](=[O:12])[C@H:8]([CH3:9])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)alanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, driedover MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)alanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:39](I)[CH3:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CCI
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Product: CCN1CCC(C(=O)N=S(C)(=O)c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 71 %

Procedure:
Product of Example 25 was ethylated using standard N-alkylating procedure with ethyl iodide to give titled compound in 71% yield.