Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)C(C(O)=O)=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[C:22]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Solvent: ClCCl
Product: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.1 mL, 81.4 mmol) was added under nitrogen dropwise over 10 minutes to a suspension of 1-benzyl-1H-indole-3-carboxylic acid (4.10 g, 16.3 mmol) in 200 mL of methylene chloride at room temperature. When the oxalyl chloride was added there was an immediate evolution of gas and within 30 minutes all of the solid had dissolved. After the addition of the oxalyl chloride the reaction was stirred at room temperature for 2 h. The solvent and excess oxalyl chloride were removed under reduced pressure. The residue was taken up in benzene and then concentrated to dryness under reduced pressure to give 1-benzyl-1H-indole-3-carbonyl chloride, which was used in the following reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>CC(O)=O.[Pd]>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:19]=[C:17]([NH2:18])[C:11]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cc([N+](=O)[O-])c(C2(C#N)CCCCC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C1(CCCCC1)C(N)=N2
Temperature: 70 °C
Yield: 7.5 %

Procedure:
1-(4,5-Dimethoxy-2-nitrophenyl)cyclohexanecarbonitrile (0.251 g, 0.865 mmol), prepared in Step 2, in AcOH (6 mL) was treated with 10% Pd/C, fitted with hydrogen balloon and heated to 70° C. for 3 hours under hydrogen atmosphere. The catalyst was filtered off and washed with EtOH. The solvent was concentrated. Purification by reverse phase HPLC afforded 17 mg (8%) of 5′,6′-dimethoxyspiro[cyclohexane-1,3′-indol]-2′-amine 1H NMR (400 MHz, DMSO) δ 7.11 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 1.88-1.84 (m 4H), 1.82-1.66 (m, 4H), 1.22 (d, J=10.2 Hz, 2H). MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Yield: 94.6 %

Procedure:
A mixed solution of the compound (0.57 g, 1.53 mmol) obtained in step 1 and 1N aqueous sodium hydroxide solution (2.289 ml, 2.29 mmol) in ethanol (5 mL) and THF (5 mL) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue. The precipitate was collected by filtration to give 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.50 g, 1.448 mmol, 95%) as a white powder.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7](O)=[O:8].[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:7](=[O:8])[C:6](=[O:5])[CH2:10][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]2)=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2ncco2)cc1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2ncco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-2-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:33]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:33][C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2nccs2)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ccc(-c3nccs3)[nH]2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a solution (5 mL) of 6-cyclopentyl-5-[4-(methylsulfonyl)phenyl]-1-(1,3-thiazol-2-yl)hexane-1,4-dione (300 mg) in N,N-dimethylformamide was added ammonium acetate (310 mg), and the mixture was stirred at 100° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (150 mg, yield 53%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 401 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:11][N:12]([CH3:13])[S:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-imidazole-4-sulfonyl chloride (0.5 g, 3.0 mmol; Matrix Scientific, Columbia, S.C.) in dichloromethane (10 mL) was added dimethylamine hydrochloride (0.245 g, 3.0 mmol) and triethylamine (1.3 mL, 9.0 mmol) at room temperature. The mixture was stirred for 16 hours at room temperature. TLC (petroleum ether/ethyl acetate=0:1) indicated the reaction was complete. The reaction mixture was washed with aq. ammonium chloride (30 mL) and extracted with dichloromethane: methanol=4:1 (3×50 mL). The combined organic phases were concentrated and precipitated from methanol to afford (I-35a) (0.36 g, 68.2%) as a white solid; 1H NMR (400 MHz, CD3OD): δ 7.74 (1 H), 7.61 (1 H), 2.68 (6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([CH:36]2[CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]2)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([CH:36]2[CH2:39][NH:38][CH2:37]2)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CNC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-(N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl)azetidine-carboxylate (Step a) (565 mg, 0.84 mmol) and 50% TFA in CH2Cl2 (6 mL). Purification by reverse phase preparative HPLC [YMC-Pack ODS-AM 250×20 mm 5 μm column, 40% to 75% CH3CN (0.1% TFA) in H2O(0.1% TFA) over 10 min] provided the title compound (TFA salt) as an amorphous white solid (420 mg). MS (ESI, pos. ion) m/z: 573 (M+1). Calcd for C29H37ClN4O4S: 572.22. Anal. Calcd for C29H37ClN4O4S 1.7C2HF3O2: C, 50.74; H, 5.09; N, 7.30, S, 4.18. Found: C. 50.47; H, 5.03; N, 7.36; S, 4.28.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:19]#CBr>C(Cl)(Cl)Cl>[C:18]([N:2]([CH2:3][CH2:4][C:5]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1)[CH3:1])#[N:19]
Reactant: N#CBr
Reactant: COc1ccc(C2(CCN(C)C)CCCC2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(CCN(C)C#N)CCCC2)cc1

Procedure:
By following the manipulative procedure outlined above in Example 12, a solution of 5.43 g of 1-(2-dimethylaminoethyl)-1-(4-methoxyphenyl)cyclopentane (the free base of Example 46) in chloroform is added to a stirred solution of 2.57 g of cyanogen bromide in chloroform to give an oil. The oil is dissolved in chlorofrom, subjected to column chromatography with a silica gel column and eluted with ether to produce an orange oil of 1-(N-cyano-N-methylaminoethyl)-1-(4-methoxyphenyl)cyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:26]=1[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C)NC(=O)c1cc(F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C)NC(=O)c1cc(F)ccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-N-(tert-butyl)-5-fluorobenzamide. MS (ESI): mass calcd. for C21H20F2N4O, 382.16; m/z found, 383.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([O:15]CC1C=CC=CC=1)=[CH:9][CH:8]=2)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([OH:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(F)c(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A mixture of methyl-N-(3,4-dichlorobenzyl)-4-fluoro-5-benzyloxyindole-2-carboxylate (8.22 g) and 5% Pd/C (200 mg) in ethyl acetate (250 ml) was stirred under a hydrogen atmosphere overnight, filtered through celite, concentrated in vacuo and purified by flash column chromatography using a gradient of 0-50% ethyl acetate/iso-hexane as eluent to give the product as a brown solid (6.18 g) 1H NMR (DMSO-d6) δ3.80(s, 3H), 5.75(s, 2H), 6.85(m, 1H), 7.00(t, 1H), 7.22(m, 2H), 7.30(m, 1H), 7.50(m,1H), 9.33(s, 1H); M/z(−) 366.2 (MH−)
Reaction SMILES: C(OC([NH:8][O:9][S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>O>[O:9]([S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:11])=[O:12])[NH2:8]
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reaction time: 0.5 h

Procedure:
To the solid product N-(tert.-butoxycarbonyl)-O-(mesitylsulfonyl)-hydroxylamine (2.1 g, 6.6 mmol) was added trifluoroacetic acid (20 mL) slowly at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes followed slowly by water (60 mL). The reaction was left at 0° C. for 15 minutes. The solid precipitated was filtered and washed several times with water until the pH of the filtrate was neutral. The white solid (1.4 g, 98%) was dried in the Buchner funnel and used immediately for the next reaction; 1H NMR (400 MHz, DMSO-d6): δ 6.73 (s, 2H), 2.48 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7]1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CN(C)C=O>[CH:21]([C:7]1[O:6][CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:22]
Reactant: COC(=O)c1cccc(-c2ccoc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccoc2C=O)c1
Reaction time: 0.5 h

Procedure:
N,N-dimethylformamide (1.7 ml) was stirred at 0° C. and to this was added dropwise phosphorus oxychloride (0.51 ml). The mixture was stirred for 30 minutes and was added a solution of methyl 3-(furan-3-yl)benzoate (1 g) in N,N-dimethylformamide (0.6 ml), and then was stirred at room temperature overnight. The reaction mixture was poured onto ice/water and then adjusted to pH 8 with an aqueous potassium carbonate solution. The product was extracted with ethyl acetate-tetrahydrofuran (1:1, 2×100 ml) and the extracts were combined, washed successively with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane:ethyl acetate (5:1) to afford methyl 3-(2-formylfuran-3-yl)benzoate (0.75 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1
Reactant: O[C@@H]1CCNC1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage 215.2) and (R)-pyrrolidin-3-ol to afford a white solid. HPLC (Condition 4) tR=5.11 min, UPLC-MS (Condition 3) tR=1.02 min, m/z=440.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[N:3]=1.C(OCCO)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[CH:5]=[C:6]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=2)[N:7]=1
Reactant: Cc1nc(Cl)cc(Nc2cccc(O)c2)n1
Reactant: COc1cccc(N)c1
Solvent: CCOCCO
Product: COc1cccc(Nc2cc(Nc3cccc(O)c3)nc(C)n2)c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
2-methyl-4-chloro-6-(3-hydroxyphenylamino)pyrimidine (0.71 g, 3.0 mmol) was added to a 2-ethoxyethanol (2.0 mL) solution of 3-methoxyaniline (0.37 g, 3.0 mmol) under a nitrogen atmosphere and the reaction mixture stirred for 5 hours at 130° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[F:23].C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C(O)(=O)C>[CH2:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH:11]1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(F)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (34.0 g, 0.321 mol) was added to a solution of tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (70 g, 0.32 mol) and acetic acid (10 mL) in ethanol (500 mL) and stirred for 30 min at room temperature. Sodiumcyanoborohydride (26.23 g, 0.417 mol) was added and stirred for 3 h. Reaction was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2×250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a minimum amount of dichloromethane (200 mL) and pH adjusted to 3-4 by adding aqueous citric acid (124 g, 0.645 mol in 1000 mL water). Layers were separated and aqueous layer was washed with dichloromethane (3×250 mL). Separated aqueous layer pH was then adjusted to 9-10 by using saturated Na2CO3 and extract with diethyl ether (2×500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product which was purified by as light yellow oil. The residue was purified by silica gel chromatography by eluting with 10-15% EtOAc/hexane to provide the desired product tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.8 (51 g, 51.52% yield). 1HNMR (400 MHz, CDCl3): δ 7.39-7.29 (m, 5H), 4.44-4.35 (m, 0.5H), 4.32-4-10 (m, 1.5H), 3.98-3.85 (m, 2H), 3.80 (d, 1H), 2.97-2.77 (m, 4H), 2.04-1.93 (m, 1H), 1.46 (s, 9H); LCMS: 92.34%, m/z=309.2 (M+1); HPLC: 95.46%; Chiral HPLC: 47.2% at 9.56 min. and 48.3% at 12.34 min. Column. AG/Chiral Pak AD-H/03, n-Hexane/EtOH (80:20).
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:14]
Reactant: CN=C=O
Reactant: CC1=NC(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)ON=C1SC(C)(C)N=C1C
Reaction time: 16 h

Procedure:
20.0 g (0.126 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are dissolved in 100 ml of chloroform. To the solution are added 15 ml (0.252 mol) of freshly distilled methyl isocyanate as well as 3 drops of triethylamine. The mixture, which warms slightly after a short time, is left to stand at room temperature for 16 hours. Subsequently, the slightly turbid solution is filtered, and the solvent and excess methyl isocyanate are distilled off in vacuo. The oily residue is purified chromatographically on 250 g of silica gel using ethyl acetate/n-hexane (1:1) for the elution. The solvent is removed by evaporation, and the resulting residue is recrystallized from methyl chloride/n-hexane/diethyl ether to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(methylcarbamoyl)oxime as white crystals, m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C1C(=O)N([O:17][C:18]([CH2:20][I:21])=O)C(=O)C1.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18](=[O:17])[CH2:20][I:21])=[CH:4][CH:3]=1
Reactant: O=C(CI)ON1C(=O)CCC1=O
Reactant: NCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(CNC(=O)CI)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
FIG. 11 illustrates the synthesis of Mass Tag (2). 4-Amino-benzylamine (Aldrich, 1 mmol), N-succinimidyl iodoacetate (Pierce, 1 mmol), and N,N-diisopropyl ethylamine (DIEA, 100 μL) were mixed in dichloromethane (10 mL) and stirred at room temperature for 1 hr. Solvent was removed under reduced pressure. The product was purified by silica gel column chromatography, eluting with hexane, ethyl acetate (20%-60%), to give 4-amino-N-iodoacetylbenzylamine (62.2% yield). 1H NMR (MeOD): 7.1 (d, 2H), 6.75 (d, 2H), 4.21 (s, 2H), 3.65 (s, 2H). [M+H]+ in MS: 291.0, calculated; 291.0, found.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][OH:9].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:21])[CH2:25][CH2:26]1
Reactant: CN1CCOCC1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.67 h
Yield: 18.8 %

Procedure:
(4-Methyl-morpholin-3-yl)-methanol (387 mg, 2.95 mmol) in THF (7.5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 354 mg, 8.85 mmol) in anhydrous THF (7.5 mL) at 0° C. and stirred under nitrogen for 40 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 1.28 g, 3.54 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. The reaction mixture was stirred for 1 h and then the solvents were removed in vacuo. The residue was suspended between water and EtOAc. The aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with aqueous Na2CO3, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give (4-methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (197 mg, 19%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([NH:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57])=[O:7]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3C#N)c(Cl)c2)c(O)n1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A solution of 3-chloro-4-(2-cyanophenoxy)benzoic acid (100 mg, 0.37 mmol) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), N-hydroxybenzotriazole (65 mg, 0.48 mmol) and triethylamine (104 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (56 mg, 0.37 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL). The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 3-chloro-4-(2-cyanophenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (34 mg, 58%) as white solid. LRMS (M+H+) m/z: calcd 407.1. found 407; 1H-NMR (300 MHz, CD3OD) δ 11.47 (s, 1H), 8.53 (m, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.90 (m, 2H), 7.68 (m, 1H), 7.29 (m, 2H), 6.93 (d, J=0.9 Hz, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4.8 Hz), 2.17 (s, 3H), 2.11 (s, 3H).