Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2Cl)s1
Yield: 16.8 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2-chlorophenylboronic acid (9 mg, 0.06 mmol) giving 3.5 mg (16%) of the title compound. MS (ESI+) calcd for C17H12ClN5O2S2 417.012094, found 417.012204.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: C1CCNC1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Pyrrolidine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-pyrrolidin-1-yl-methanone. LC-MS: m/e 394 (MH+).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(Cl)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.9 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 13.5 g of 4-chlorobenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 149°-150° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.95 (dd, 1H), 3.60 (dd, 2H), 5.67 (dd, 1H), 7.33-7.44 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:11]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]#[CH:9]
Reactant: C#CCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.2 %

Procedure:
2-bromophenol (6.12 g, 35.3 mmol) and propargyl bromide (5.67 g, 38.1 mmol) were dissolved in DMF (34 ml). This solution was added with potassium carbonate (10.9 g, 78.9 mmol) and stirred at room temperature for 14 hours. The reaction solution was added with ethyl acetate, sequentially washed with water and saturated sodium chloride water, and dried with anhydrous sodium sulfate. Concentration under reduced pressure was carried out to obtain the title compound (7.91 g, 98.0%) as a yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[C:14]3N=N2)=[N:6][CH:7]=1.[OH2:28].[OH-].[NH4+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:15]2[C:14]([OH:28])=[CH:19][C:18]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCn1nnc2cc(Cc3cccnc3)cnc21
Reactant: O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1O

Procedure:
3-[3-(5-Bromo-3-methylpyrid-2-yl)propyl]-6-(3-pyridylmethyl)-3H-1,2,3-triazolo[5,4-b]pyridine (2.68 g) was added in portions over 15 minutes to hot (190°-200° C.) stirred polyphosphoric acid (10.45 g). The stirred reaction was heated at 190°-200° C. for a further 45 minutes, water (20 ml) was added to the hot reaction mixture, the solution was neutralised with concentrated ammonium hydroxide and allowed to cool. The pH was then raised to 10, chloroform extraction of the aqueous mixture gave a brown solid. This solid was recrystallised from ethanol/ether giving buff crystals (1.64 g). These were chromatographed on silica in methanol/chloroform 1:9, the product was then recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (1.4 g) (off-white crystals), m.p. 141°-143° C.
Reaction SMILES: O=[C:2]1[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:13](=O)[N:12]2[CH2:21][CH2:22][S:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][N:3]1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]2.B#B>O1CCCC1>[N:3]12[CH2:28][CH2:27][S:26][CH2:25][CH2:24][S:23][CH2:22][CH2:21][N:12]([CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:2]2
Reactant: O=C1COCCOCC(=O)N2CCOCCOCCN1CCSCCSCC2
Agent: B#B
Solvent: C1CCOC1
Product: C1COCCN2CCOCCOCCN(CCO1)CCSCCSCC2
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 1.6 g. of the bicyclic diamide obtained in Example 30 in 30 ml. anhydrous tetrahydrofuran is slowly added to 20 ml. of the fresh prepared diborane solution (1.5 N) under nitrogen atmosphere and a temperature of 0° C. The mixture is stirred two hours at reflux temperature. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotary evaporator under vacuum. This residue is treated with 50 ml. 6 N hydrochloric acid under heating at reflux for two hours and a solution is obtained. The mixture is evaporated under vacuum on a rotary evaporator (water bath 80°-100° C.). The residue is dissolved in 50 ml. water and the solution is passed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The water is evaporated. The residue is dried in vacuum (0.1 mm. Hg) and recrystallized from a benzene and heptane mixture, yielding the desired compound.
Reaction SMILES: [C:1](=[O:3])=[O:2].C1COCC1.[Li][C:10]1[S:20][C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=1>O>[S:20]1[C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=[C:10]1[C:1]([OH:3])=[O:2]
Reactant: O=C=O
Reactant: [Li]c1cc2sc3sccc3c2s1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2sc3sccc3c2s1
Temperature: -78 °C
Yield: 61 %

Procedure:
Carbon dioxide was added in small lumps to a flask against a fast flow of nitrogen. The flask was then sealed under a nitrogen bubbler and cooled to the −78° C. THF was added to cover the CO2 and the mixture stirred. The cooled lithiodithienothiophene was added dropwise via syringe and a violent reaction was observed resulting in the formation of a yellow suspension. Once addition was complete the mixture was allowed to warm to r.t. during which time the mixture turned to an off white colour. After stirring for a further 30 min. water (30 cm3) was added and the mixture turned to a light green/brown solution. This was washed with ether (2×20 cm3) and the organics discarded. The aqueous layer was acidified by the addition of HCl (10 cm3, 5 M) which precipitated out a fine yellow solid. Recrystallisation was attempted in 33% acetic acid. A fine, insoluble suspension remained after heating and this was left to further crystallise overnight to give the title compound as a fine yellow/green powder (286 mg, 61%); δH 7.31, (1H, d, J5.1), 7.56 (2H, d, J5.1), 7.94 (1H, s); v max/cm−1 (KBr) 3090 m, 2823 m, 2559 m, 1652 s, 1504 s, 1470 w, 1428 s, 1311 s, 1265 m, 1164 m, 928 s, 750 s, 716 s and 602 s; m.p. 276° C. (sublimes) m.p.(lit.reference 29) 275-277° C.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25]O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a mixture of 1.0 g (6.37 mmole) of 3-fluoro-4-nitrophenol, 1.78 g (8.27 mmole) of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 2.81 g (10.71 mmole) of triphenylphosphine and 50 mL of tetrahydrofuran was added 1.67 mL (10.71 mmole) of diethylazodicarboxylate. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 2.16 g of 4-(3-fluoro-4-nitro-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (IV.23).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([OH:33])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C=O)C>[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(NC1CCCc2c(O)cccc21)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 57.1 %

Procedure:
A solution of NaH (60% oil, 66 mg) and 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.55 g) in DMF (10 ml) was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl bromoacetate (0.26 g). After being stirred for 7 hours at room temperature, the solution was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:15])[CH2:7][CH2:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:15])[CH2:7][CH:8]=[CH:9][C:10]([Cl:12])([Cl:13])[Cl:11])=[CH:4][CH:3]=1
Reactant: O=C(CCC(O)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC=CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 60 h

Procedure:
1-p-Chlorophenacyl-2-hydroxy-3,3,3-trichloropropane (450 mg) was dissolved in benzene and p-toluene sulphonic acid monohydrate (40 mg) added. The solution was refluxed with a Dean and Stark apparatus and any reaction followed by tlc. After 5 hours refluxing tlc revealed that only starting material was present. The solution was treated with a second portion of p-toluene sulphonic acid (100 mg) and further refluxed for 5 hours. The solution was allowed to stand over 60 hours and evaporated to dryness. tlc Analysis (10% Et.AC./petrol) revealed a new product (Rf 0.8) with no starting material remaining. The solution was taken up in ethyl acetate and passed down a short alumina column (to remove pTSA). Elution with 25% Et.Ac./petrol yielded the product. Yield 200 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nnc(C(F)(F)F)s1
Product: O=C(Nc1nnc(C(F)(F)F)s1)c1cc(Br)ccc1O
Yield: 80.2 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C:4]3[CH:3]=[CH:2][N:30]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Yield: 59.3 %

Procedure:
A solution of 4.94 g of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone and 220 ml of p-toluenesulfonic acid in 200 ml of anhydrous toluene was heated on a water separator. A solution of 6.39 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes, during which the solvent was reduced to a volume of 40 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 3.42 g (60%) of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
To a mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in the above (1)) 500 mg and triethylamine 0.58 ml in dimethylformamide 3 ml is added 3-chloro-4-methoxybenzylamine 359 mg in dimethylformamide 3 ml at room temperature over a period of 15 minutes, and the mixture is stirred for 4 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-chloro-2-methylthiopyrimidine as a slightly brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1cccc(Oc2ccccc2)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cccc1Oc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 2-methyl-6-phenoxy-benzoic acid (19.9 mmol, 4.54 g), methanol (20 mL), and concentrated sulfuric acid (1.5 mL) was refluxed with stirring for 18 h before it was concentrated in vacuo. To the residue was added water (50 mL) and the mixture was neutralized by adding small portions of NaHCO3 with stirring. Subsequently, the mixture was extracted with ethyl acetate (1×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:ethyl acetate=7:3 as the eluent gave the title compound as a yellowish oil (2.16 g); MS-(+)-ion: M+1=242.8.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][S:3]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:4]2/[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][C:2](=[O:1])[S:3]/2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl N-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinate (4.41 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (5.00 g) in 2-propanol (50 mL) was added piperidinium acetate (2.14 g). The reaction mixture was stirred at 70° C. for 3 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (5.25 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].Br[CH2:22][C:23]([N:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].[H-].[Na+]>CN(C=O)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:22][C:23]([N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)N(c1ccccc1)c1ccccc1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CNC1CCN(C(c2ccccc2)c2ccccc2)C1=O)N(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol in dry DMF (15 ml) was added 2-bromo-N,N-diphenyl acetamide (0.24 g, 0.82 mmol) and NaH (50 mg) under nitrogen. The reaction mixture was heated at 100 degrees overnight. After cooling, the solvent was evaporated and residue was taken up with ethyl acetate (50 ml) and washed with water (2×10 ml). The organic was dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give desired product in 73% yield.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.Br[CH2:10][C:11]#[N:12].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:10][C:11]#[N:12])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
A mixture of p-bromophenol (2.61 g; 15.1 mmol), bromoacetonitrile (1.11 mL; 15.9 mmol), and Cs2CO3 (7.40 g; 22.7 mmol) in anhyd MeCN (25 mL) was heated at 80° C., under N2 overnight. The mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. The residue was dissolved in a minimal amount of EtOAc/hexanes and filtered through a short pad of silica gel (EtOAc/hexanes eluent), affording the title compound as a colorless, waxy solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.75 (s, 2H), 6.88 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][N:11]=[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CNC(=O)c1ccnc(I)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)NC)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
In a round-bottomed flask, 2-iodo-N-methylisonicotinamide (0.18 g, 0.69 mmol) was dissolved in THF (3.9 mL) and sodium hydride (60% dispersion in mineral oil, 33 mg, 0.83 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.39 mL, 0.780 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 40 min then tributylchlorostannane (0.22 mL, 0.81 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/Hexanes (contains 1% Triethylamine) (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 89 mg (31%) of N-methyl-2-tributylstannanyl-isonicotinamide as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19](O)=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
O-benzyl-N-(t-butoxycarbonyl)-L-serine (2 g) was dissolved in tetrahydrofuran (20 ml), triethylamine (1.22 ml) was added, and ethyl chloroformate (713 μl) was further added dropwise at 0° C. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was filtered, and one piece of ice was added to the filtrate. Sodium borohydride (515 mg) was further added, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate (1.7 g)