Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:36])[F:37])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH3:39])[CH2:14][CH2:15]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)c(F)c2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.041 mL, 0.50 mmol) was added to a suspension of 2-(2-(2-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (7) (0.046 g, 0.092 mmol) in anhydrous MeOH (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.19 g, 0.10 mmol) was then added in one portion and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). Solid NaHCO3 was added until the formation of gas ceased, then the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 8 as a white solid (0.043 g, 92%); 1H NMR (400 MHz, d4-MeOH) δ 8.58 (s, 1H), 7.66 (dd, J=13.2, 2.0 Hz, 1H), 7.37 (dd, J=8.5, 2.0 Hz, 1H), 7.28-7.14 (m, 5H), 3.68 (s, 2H), 3.20-3.12 (m, 2H), 3.13-3.04 (m, 2H), 3.01 (d, J=12.0 Hz, 2H), 2.90-2.76 (m, 1H), 2.34 (s, 3H), 2.24-2.12 (m, 2H), 1.90-1.77 (m, 4H). LCMS-A rt 4.888 min; m/z 516.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:22][C:23]1[N:28]=[C:27]([C:29]2[C:30]([CH3:39])=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH:26]=[C:25]([S:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[CH:45]([NH2:49])[CH2:46][CH2:47][NH2:48])[N:24]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:22][C:23]1[N:24]=[C:25]2[CH:26]=[C:27]([C:29]3[CH:37]=[C:33]([C:34](=[O:36])[NH:48][CH2:47][CH2:46][CH:45]([NH:49][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[C:44](=[O:50])[NH:43][CH2:42][CH2:41][S:40]2)[C:32]([CH3:38])=[CH:31][C:30]=3[CH3:39])[N:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)c(-c2cc(SCCNC(=O)C(N)CCN)nc(N)n2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2cc1C(=O)NCCC(NC(=O)C(F)(F)F)C(=O)NCCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
5-{2-Amino-6-[2-(2,4-diaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tri(trifluoroacetate) (60 mg, 0.079 mmol) obtained in Step 3 of Example 3-8 and 1-hydroxybenzotriazole (43 mg, 0.316 mmol) were dissolved in N,N-dimethylformamide (46 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.316 mmol) and diisopropylethylamine (8.3 μl, 0.473 mmol) were added to the solution, and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and then sequentially washed with a saturated aqueous sodium bicarbonate solution, water (three times), and a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous sodium sulfate, the inorganic salt was filtered and washed with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=10:1) to yield N-(4-amino-18,20-dimethyl-11,16-dioxo-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaen-12-yl)-2,2,2-trifluoroacetamide (Compound 75) (12 mg) as a white solid material.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:9].[Br:10]CC(C1C=C(C)C=CN=1)=O>>[BrH:10].[Br:9][CH2:2][C:1]([C:4]1[S:8][CH:7]=[N:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cncs1
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: O=C(CBr)c1cncs1

Procedure:
* 5-bromoacetylthiazole hydrobromide was prepared from 5-acetylthiazole according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)(=[O:35])=[O:36]
Reactant: COC(=O)CCCC=C(c1ccc(CCN)cc1)c1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)NCCc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.24 g of methyl 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoate, 2.2 g of 2,4,6-trimethylbenzenesulphonic acid chloride and 100 ml of triethylamine in 50 ml of dichloromethane is stirred for 30 minutes at ambient temperature. Then the reaction mixture is washed twice with water, dried and evaporated down. The residue is purified over a silica gel column using ethyl acetate. The crude product obtain is heated in a mixture of 32 ml of ethanol and 5 ml of 4N sodium hydroxide solution for 30 minutes to 50° to 60° C. The reaction mixture is evaporated down, the residue is taken up in 50 ml of water and washed with ethyl acetate. The aqueous phase is adjusted to pH 5 by the addition of citric acid and extracted twice with ethyl acetate. The organic phase is dried, evaporated down and the residue is chromatographed over a silica gel column using ethyl acetate. The crude product is then recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:15])[C:13]#[CH:14])[CH3:10].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=1[F:24]>C1COCC1.C(OCC)C.[Zn+2].[Br-].[Br-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:15])[C:13]#[C:14][C:20]1[CH:21]=[CH:22][C:17]([F:16])=[C:18]([F:24])[CH:19]=1)[CH3:10]
Reactant: C#CC(=O)OCC
Reactant: Fc1ccc(I)cc1F
Agent: [Pd]
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C#Cc1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a four neck flask was charged with THF (135 ml) and 2 M LDA in THF (60.9 ml, 0.12 mol, 1.18 eq.) and cooled to −78° C. Propynoic acid ethyl ester (12.2 g, 0.12 mol, 1.18 eq.) dissolved in THF (36 ml) was added dropwise within 30 min. Then, ZnBr2 (28.5 g, 0.12 mol, 1.2 eq.) dissolved in THF (45 ml) was added dropwise within 30 min. After the addition of 1,2-Difluoro-4-iodo-benzene (25.0 g, 0.10 mol) and tetrakis(triphenylphosphine) palladium(0) (6.02 g, 5.15 mmol, 5 mol %), the reaction mixture was allowed to warm to r.t. and stirred for another 3 h at the same temperature. The reaction mixture was diluted with diethylether and washed with saturated aqueous NH4I, saturated aqueous NaHCO3 and brine. The organic phase was dried with Na2SO4, concentrated under reduced pressure and dried under vacuum. The residue was purified by silica gel filtration (heptane/ethyl acetate 98:2) to yield 16.6 g (76%) of Vc as light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CO.O>C(Cl)Cl>[F:33][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Yield: 9.6 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (150 mg, 0.352 mmol) and SELECTFLUOR® (150 mg, 0.422 mmol) in DCM (1 mL) and MeOH (1 mL) was stirred at RT overnight. Water was subsequently added and the mixture was extracted with CHCl3 (3×). The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by preparative HPLC to give the title compound (15 mg, 9.60%). [M+H] calc'd for C22H29FN6O3, 445; found, 445.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH3:12]>>[CH2:10]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[CH2:11][CH3:12]
Reactant: Oc1cccc(Br)c1
Reactant: CCCBr
Product: CCCOc1cccc(Br)c1

Procedure:
3-Bromophenol and 1-bromopropane are reacted analogously to Example 1 to give 3-propoxybromobenzene. ##STR25## 3-Propoxybromobenzene is converted analogously to Example 1 into 3-propoxybenzeneboronic acid. ##STR26##
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][NH2:29]>CS(C)=O.CS(C)=O.C1CN2C(=NCCC2)C1>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:29][CH2:28][CH2:27][NH:26][C:2](=[O:3])[CH2:1][N:8]([CH2:7][C:5]([OH:4])=[O:6])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: NCCN
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 48 h
Yield: 30.4 %

Procedure:
A 500 mL three-neck flash was charged with 150 mL of dry DMSO and the flask flushed with nitrogen. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.00 g, 5.60 mmol) in 125 mL of DMSO, and 1,2-diaminoethane (0.336 g, 5,60 mmol) in DMSO/DBN (122 mL/3 mL). The solutions were added simultaneously to the flask at ambient temperature at a rate of 40 mL/hour. After the addition was complete, the reaction mixture was allowed to stir for 48 hours, concentrated under vacuum to 10 mL and 5 mL of water added. This solution, at pH 10.9, was applied to AG1-X8 (100-200 mesh, OAc-) resin, and the column eluted with 0.5N acetic acid to yield 0.71 g (30%) product as a white solid after acetic acid removal and lyophilization.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH:16]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxyindole (2.66 g, 20.0 mmol), t-butyl 3-hydroxy-1-pyrrolidinecarboxylate (7.5 g, 40.0 mmol) and triphenylphosphine (φ3P) (10.5 g 40.0 mmol) in THF is treated with diethyl azodicarboxylate (DEAC)(6.3 ml, 40.0 mmol) under nitrogen at room temperature, stirred for 2 h at room temperature and concentrated in vacuo. The resultant residue is stirred under ether, cooled and filtered. The filtercake is washed with cold ether. The filtrates are combined and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, EtOAc/hexane: 2/80) to give the title compound as a white solid, 3.98 g, mp 164-165° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]1(=[O:25])[NH:23][C:22](=[O:24])[CH:21]=[CH:20]1>CO>[CH:5]1[C:4]2[CH2:3][C:2]3[CH:10]4[CH:18]([C:17]5[C:12]([NH:11]4)=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:21]4[C:22](=[O:24])[NH:23][C:19](=[O:25])[CH:20]4[C:1]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Reactant: O=C1C=CC(=O)N1
Solvent: CO
Product: O=C1NC(=O)C2C1C1=C(Cc3ccccc31)C1Nc3ccccc3C12
Yield: 62.3 %

Procedure:
A mixture of 2-(2-indenyl)indole (1.0 g, 4.3 mmol) and maleimide (525 mg, 5.41 mmol) in a 10 cm sealed reaction vial was heated at 180°-190° C. for 30 min. After cooling the reaction to ambient temperature, MeOH (5 mL) was added. The product was collected to give 880 mg (62%) of a white solid product with a m.p. of 254°-255° C. (MeOH). The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): 63.1-3.4 (m, 2H), 3.8 (m, 2H), 3.95 (t, 1H), 4.35 (d, 1H), 6.9-7.4 (m, 7H), 7.75 (d, 1H), 11.05 (s, 1H), 11.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=O)=[CH:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])=[CH:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(=O)n(Cc3ccc(Cl)cc3)c3ccccc23)S1
Yield: 50.5 %

Procedure:
1.50 g of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-carboxaldehyde and 0.826 g of 2,4-thiazolidinedione were suspended in 30 ml of toluene. Five drops of piperidine and five drops of acetic acid were added, followed by heating and refluxing for 6 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 1.01 g (50% yield) of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-ylmethylidene]thiazolidine-2,4-dione as a light-brown powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[CH3:18][C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:29]([C:28]2[CH:27]=[CH:26][C:25]([N:20]3[C@H:19]([CH3:18])[CH2:23][O:22][C:21]3=[O:24])=[CH:33][CH:32]=2)=[O:30])[CH2:16][CH2:17]1)=[O:11]
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C)c1
Yield: 104.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (2,4-dimethylphenyl)piperidin-4-ylmethanone hydrochloride (253 mg) and (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (211 mg) described in Preparation Example 37, the title compound (419 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH3:38])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Product: COCCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and 2-methoxy-N-methylethanamine (183 mg, 2.05 mmol). Pale yellow solid (75 mg, 86%). MS (ESI): 427 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:36]1[C:39]2([CH2:42][NH:41][CH2:40]2)[CH2:38][O:37]1>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:41]3[CH2:42][C:39]4([CH2:36][O:37][CH2:38]4)[CH2:40]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C1NCC12COC2
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Agent: O=C(O)C(=O)O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CC3(COC3)C2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) (CAN 1045709-32-7) as starting materials and isolated (8 mg, 10%); MS (ESI, m/z): 496.5 (M+H+).
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:22][CH:21]=1
Reactant: C#CC(=Nc1ccccc1)SCC1CCCCC1
Reactant: Fc1ccc(S)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(SC=CC(=Nc2ccccc2)SCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
Cyclohexylmethyl N-phenylpropynthioimidate (0.34 g) was dissolved to chloroform (8 mL), chloroform (2 mL) solution of 4-fluorothiophenol (0.14 g) was added dropwise under ice-cooling, and then it was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by medium pressure HPLC (hexane/ethyl acetate=98/2) to obtain cyclohexylmethyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.25 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]3[CH3:22])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:18][C@@H:17]3[CH3:22])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C1COC1
Reactant: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)c[nH]c2=O)nc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)c[nH]c2=O)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of 138b (1.0 g, 3.1 mmol) in methanol (35 mL) was added oxetan-3-one (669.6 mg, 9.3 mmol), NaBH3CN (585.9 mg, 9.3 mmol), and ZnCl2 (1.26 g, 9.3 mmol). The reaction was stirred at 30° C. for 2 h. The mixture was evaporated under reduced pressure and the residue diluted with water (20 mL). It was then extracted with dichloromethane (3×30 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol to afford 138c (291 mg, 25%) as a red solid. MS-ESI: [M+H]+ 376.3
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Product: O=C(Cl)c1cc(F)c(Cl)nc1Cl

Procedure:
A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5.00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)#N>O>[CH:4]1[CH:5]=[CH:6][C:1]2[N:8]=[C:9]([C:11]3[N:12]=[CH:13][S:14][CH:15]=3)[NH:7][C:2]=2[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: N#Cc1cscn1
Solvent: O
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 50 °C
Yield: 89.3 %

Procedure:
The product, thiabendazole, precipitated as it was formed in the reaction mixture. The reaction was monitored by gas chromatography and determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were negligible. The reaction mass was allowed to cool to 50° C. and 150 ml of 50° C. deionized water was added to thin the mixture before being vacuum filtered using a medium fritted glass filter. The solid product was washed four times with 300 ml portions of deionized water. The washed precipitate was dried overnight in a vacuum oven under 15-20" Hg and at a temperature of 80°-90° C. A total of 89.77 grams of thiabendazole were obtained which corresponds to an 89.3% yield. The color of dry thiabendazole was cream. High Performance Liquid Chromatography (HPLC) using a Hewlett-Packard Model 1090M showed that the purity was 98.77% (based on % area).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:25]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1-(4-(methoxy(methyl)carbamoyl)phenyl)cyclobutyl)carbamate (0.5 g, 1 eq.) in tetrahydrofuran (THF) (5 mL) cooled to 0° C. was slowly added a 1 M solution of methylmagnesium bromide in ether (4.5 mL, 3 eq.). The reaction mixture was stirred at room temperature overnight then quenched by the addition of saturated aqueous ammonium chloride (15 mL). The mixture was extracted with dichloromethane (2×25 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (15% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-acetylphenyl)cyclobutyl)carbamate as a colorless oil which solidified upon standing (261 mg, 60%). 1H NMR (DMSO-d6) 400 MHz δ 7.91 (d, J=8.0 Hz, 2H), 7.74 (br. s, 1 H), 7.50 (d, J=8.4 Hz, 2H), 2.56 (s, 3H), 2.45-2.32 (m, 4H), 2.06-1.94 (m, 1H), 1.86-1.75 (m, 1H), 1.33 (s, 9H).