Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:38][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:36])([F:37])[F:35])[CH:28]=2)[N:23]=1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
17 mg (0.42 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 87 mg (0.40 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 120 mg (0.40 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 12 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 138 mg (71%) of the title compound as almost colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][C:24]1[O:28][N:27]=[C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:30]([NH:29][C:26]2[CH:25]=[C:24]([CH3:23])[O:28][N:27]=2)=[O:31])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C)on4)c3)c2cc1OC
Yield: 25 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 5-methylisoxazol-3-ylcarbamate from the previous step (98 mg, 0.42 mmol) were reacted using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea (31 mg, 0.074 mmol, 25%). 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 2H), 7.26 (d, 1H), 6.97 (d, 1H), 6.51 (s, 1H), 3.99 (s, 6H), 2.35 (s, 3H); LC-MS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64]([O:68][C:69]([N:71]1[CH:76]2[CH2:77][CH2:78][CH:72]1[CH2:73][NH:74][CH2:75]2)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CN(C=O)C>[C:64]([O:68][C:69]([N:71]1[CH:72]2[CH2:78][CH2:77][CH:76]1[CH2:75][N:74]([C:21]([C:20]1[CH:19]=[N:18][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:25][CH:24]=1)=[O:22])[CH2:73]2)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a 1 mL DMF solution of 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (50 mg, 0.122 mmol) was added DIPEA (32 mg, 0.043 mmol) and HBTU (49 mg, 0.129 mmol). After stirring for 15 m at room temperature 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (31.2 mg, 0.147 mmol) was added and the reaction mixture was left to stir at room temperature for 4 h. The reaction was quenched by pouring into brine and extracted with EtOAc. The organic extracts were dried with Na2SO4, filtered and concentrated. The crude product was purified by NP-LC (Analogix, 10% MeOH in EtOAc) to yield 3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol). MS m/z 603.5 (M+H)+.
Reaction SMILES: NC(CS)C(O)=O.C(O)(C(F)(F)F)=O.[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:49])[F:48])[CH:16]([CH3:18])[CH3:17]>O>[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([OH:40])=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:48])[F:49])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 2-amino-3-mercaptopropanoic acid (0.042 g, 0.347 mmol) in TFA (600 μL, 7.79 mmol) was added to neat tert-butyl 2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.058 g, 0.116 mmol). The reaction mixture was stirred for 1 h at room temperature and then diluted with ice and water causing a tan solid to precipitate. The aqueous mixture was decanted off of the tan solid and the solid was rinsed with water. The solid was dried under vacuum to give the title compound (37 mg). LCMS m/z=446.7 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.87-1.98 (m, 1H), 2.16-2.26 (m, 1H), 2.53-2.82 (m, 5H), 3.53-3.62 (m, 1H), 3.92-4.00 (m, 1H), 4.06-4.14 (m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.75 (d, J=1.1 Hz, 1H).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[C:19]#[N:20]>CCOC(C)=O>[CH2:8]([O:15][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:18]=1[C:19]#[N:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Intermediate B, Step 1: A 250-mL round bottom flask containing a magnetic stir bar and fitted with a condenser and a inert gas inlet was charged successively with sodium hydride (60% dispersion in mineral oil, 1.32 g, 33.0 mmol), THF (46 mL) and a THF (46 mL) solution of benzyl alcohol (2.86 mL, 27.5 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (5.2 g, 27.5 mmol). The resulting solution was warmed to 60° C. for 3 h, then cooled to RT, diluted with EtOAc (200 mL) and washed with water (2×100 mL) and brine (60 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator to give crude 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.32 g, 26.4 mmol, 96% yield) as a colorless oil. LC/MS [M+H]+=278.07. 1H-NMR (400 MHz, CDCl3) δ=7.89 (s, 1H), 7.78 (d, J=12.0 Hz, 1H), 7.5-7.3 (m, 5H), 7.12 (d, J=8.0 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 62.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10 g) and 4-ethylaniline (8.12 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (10.7 g) was obtained. melting point: 64–66° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[F:1]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (16.0 g, 0.046 mol) and NH4Cl (6.0 g, 0.11 mol) in EtOH/H2O (150 mL, v/v=4:1) was added iron powder (12.4 g, 0.22 mol) at rt. The reaction mixture was heated to reflux for 2 h, then cooled down to rt. Celite (10 g) was then added and stirring for 30 min. The mixture was filtered and the solid was washed with MeOH (20 mL×3) and DCM (20 mL×3). The filtrate was washed with 30 mL of saturated NaHCO3 aqueous. The aqueous phase was extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over Na2SO4, and concentrated in vacuo to give a yellow solid (0.9 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].O.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH:12]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
1-(4-Methoxyphenyl)-1-buten-3-one (35e, 0.29 g, 1.6 mmol) was dissolved in methanol (5 ml) and stirred for 5 min at room temperature. A solution of sodium hydroxide (0.14 g, 3.5 mmol) and water (5 ml) was added and the mixture stirred for 30 min at room temperature. Benzaldehyde (1b, 0.17 ml, 1.7 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 0.41 g (94%) of a yellow solid: mp 85-89° C. [expected mp 118-119° C.]; 1H NMR: δ 3.82 (s, 3H), 6.91 (d, 2H, J=8.5 Hz), 6.94 (d, 1H, J=15.9 Hz), 7.06 (d, 1H, J=16.1 Hz), 7.38 (m, 4H), 7.57 (m, 3H), 7.71 (dd, 2H, J=15.9, 2.0 Hz); 13C NMR: δ 55.4, 114.4, 123.3, 125.5, 127.4, 128.2, 128.8, 130.0, 130.2, 134.8, 142.6, 143.0, 161.5, 188.6.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:23][OH:24])=[C:19]([CH2:21][OH:22])[CH:20]=3)=[CH:10][CH:9]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[OH:22][CH2:21][C:19]1[CH:20]=[C:15]([CH:16]=[CH:17][C:18]=1[CH2:23][OH:24])[O:14][CH2:13][C:11]1[S:12][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][CH:10]=1
Reactant: CCC1(c2ccc(COc3ccc(CO)c(CO)c3)s2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)c1ccc(COc2ccc(CO)c(CO)c2)s1

Procedure:
8 g (22.8 mmol) of {5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]-2-hydroxymethylphenyl}methanol are dissolved in 75 mL of water and 75 mL of acetone. 1 g of para-toluenesulphonic acid is then added and the reaction medium is refluxed for 1 hour. The reaction medium is treated with sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried and concentrated under reduced pressure. A white powder (m.p.=123° C.) is obtained (m=6.9 g; Y=100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:4].[CH3:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C(OCC)(=O)C>[CH3:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:41])[NH:1][CH2:2][C:3]([N:5]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[O:4])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1C(=O)N1CCCc2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)N2CCCc3ccccc32)c1
Yield: 45.6 %

Procedure:
Using a procedure similar to that described in Example 27, but starting with tert-butyl 2-{2-amino-N-[2-(1,2,3,4-tetrahydro-1-quinolyl)carbonylphenyl]acetamido}acetate (2 g) and 3-methylphenyl isocyanate (0.63 g), and after recrysallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-[2-(1,2,3,4-tetrahydro-1-quinolyl)carbonylphenyl]acetamido}acetate (1.2 g), m.p. 160° C., is obtained.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[N:11][C:12]([Cl:16])=[N:13][C:14]=1[CH3:15]>C1COCC1>[Br:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([Cl:16])=[N:11][C:10]=1[O:5][CH:3]1[CH2:4][O:1][CH2:2]1
Reactant: Cc1nc(Cl)nc(Cl)c1Br
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(OC2COC2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
To a solution of oxetan-3-ol (0.368 g, 4.96 mmol) in anhydrous THF (16 mL) at 0° C. was added NaH (60% in mineral oil, 213 mg, 5.32 mmol). The mixture was stirred at 0° C. for 20 min, then 5-bromo-2,4-dichloro-6-methylpyrimidine (0.800 g, 3.30 mmol) was added to the mixture at 0° C. and stirred for 5 min. After this time the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 1-25% EtOAc in hexanes in 40 min) to give the title compound (0.566 g, 61%) as a white oil. 1H NMR (CDCl3, 500 MHz) δ 5.71-5.66 (m, 1H), 5.030-4.99 (m, 2H), 4.79-4.76 (m, 2H), 2.59 (s, 3H).
Reaction SMILES: [N:1]1([C@H:10]2[CH2:13][C@H:12]([NH2:14])[CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.Cl[C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>CN(C)C1C=CN=CC=1.CS(C)=O>[N:1]1([C@H:10]2[CH2:11][C@H:12]([NH:14][C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH2:13]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@H]1C[C@H](n2ccc3cccnc32)C1
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2c(c1)ccn2[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C

Procedure:
trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutanamine (78 mg, 0.42 mmol), 4-dimethylaminopyridine (3.56 mg, 0.029 mmol), N,N-diisopropylethylamine (159 μl, 0.916 mmol) and 2-chlorobenzothiazole (81 μl, 0.625 mmol) were added in a round bottomed flask, followed by dry DMSO (833 μl). The mixture was sealed and heated at 110° C. for 16 h. The reaction mixture was partitioned between water, saturated ammonium chloride and ethyl acetate. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using ISCO (0-60% EtOAc in hexane), gave N-(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (23 mg, 0.072 mmol, 17% yield) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 2.77 (ddd, J=14.04, 8.46, 3.72 Hz, 2 H) 2.96-3.14 (m, 2 H) 4.56 (dt, J=7.43, 3.72 Hz, 1 H) 5.59-5.76 (m, 1 H) 6.54 (d, J=3.52 Hz, 1 H) 7.04-7.17 (m, 2 H) 7.28-7.36 (m, 1 H) 7.45 (d, J=3.72 Hz, 1 H) 7.60 (t, J=8.51 Hz, 2 H) 7.92 (dd, J=7.82, 1.37 Hz, 1 H) 8.32 (dd, J=4.69, 1.37 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].C(N(CC)CC)C.[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25])=[O:40]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1sccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1′-(3-aminopropyl)spiro[furo[2,3-f]-[1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.05 g, 0.13 mmol) in dichloromethane (4.00 mL) was added triethylamine (0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g, 0.12 mmol) at 0° C. The mixture was stirred for 2 h, washed with 15% HCl solution and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the product was precipitated with the addition of hexane. The white solid was collected by filtration and dried in vacuo to yield the title compound (0.04 g) in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27- (m, 1H), 7.17 (d, 1H), 7.08-7.03- (m, 1H), 6.93 (t, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79- (m, 2H), 3.53-3.36- (m, 2H), 2.04-1.93- (m, 2H); 13C NMR (75 MHz, CDCl3) 178.3, 160.6, 156.0, 149.0, 142.4, 141.8, 132.5, 129.4, 129.2, 129.1, 124.2, 123.7, 123.6, 119.2, 108.5, 102.9, 101.6, 93.7, 80.5, 58.3, 37.4, 36.5, 27.3; MS (ES+) m/z 483 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:15][C:13]([CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(CCO)cc1

Procedure:
The hapten p-(carboxymethyl)ritodrine (Hapten E) was prepared in four steps according to FIG. 7 of the accompanying drawings, from 2-(4-hydroxyphenyl)ethanol 17. The reaction of 17 with t-butyl bromoacetate in acetonitrile in the presence of potassium carbonate at 60° C. gives 2-[4-(t-butoxycarbonylmethoxy)phenyl]ethanol 18. The oxidation of the alcohol 18 with pyridinium chlorochromate (pcc) in dichloromethane gives the 2-[4-(t-butoxycarbonylmethoxy)phenyl]ethanal 19. The ester 20, obtained by condensation of the aldehyde 19 with α-(1-aminoethyl)-4-hydroxybenzyl alcohol hydrochloride 13 in methanol in the presence of sodium cyanoborohydride and triethylamine. Deprotection of the t-butyl protecting group of the ester 20 with 4 M HCl in dioxane at room temperature gave Hapten E in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CN(C)C=O>[OH:34][CH2:33][CH2:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: OCCBr
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(O)cc3o2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCCO)cc3o2)cc1OC
Yield: 55 %

Procedure:
7-hydroxy-3',4',5-trimethoxy flavone (200 mg, 0.61 mmol) was dissolved in dimethylformamide and hereto was added potassium carbonate (253 mg, 3 equivalents) and 2-bromoethanol (65 μl, 1.5 equivalents). After the reaction mixture was refluxed for 3~4 hours, the solvent was removed under reduced pressure and the residue was diluted with chloroform and washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the residue was column-chromatograped to give 125 mg of the product (55%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([CH2:20][OH:21])[CH2:17][CH2:16][N:15]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:10]=[CH:11][C:12]=1[F:13].C(N(CC)CC)C.N12CCN(CC1)CC2>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:16][N:15]2[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC[C@H](CO)C[C@@H]1c1ccc(F)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccc(F)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
Methanesulfonyl chloride (74 mg, 0.65 mmol) was added to a mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (233 mg, 0.64 mmol), triethylamine (233 mg, 1.7 mmol), and 1,4-diazabicyclo[2.2.2]octane (15 mg, 0.13 mmol) in toluene (10 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 15 minutes, and at room temperature for another 15 minutes. The reaction mixture was then quenched with a cold mixture of water and ethyl acetate. The organic portion was separated, washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (271 mg, 96% yield). MS (EI) for C21H23F2NO5S: 440 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncnc2)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncnc2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To 90 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine, 31 mg of 2-aminopyrazine, 31 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 116 mg of tripotassium phosphate and 28 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 2 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 3 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 30 mg of the objective compound as pale yellow powder.