Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6](I)=[CH:5][Se:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[C:32]1([C:38]#[CH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(OC)(C)C.[Cu]I.CN(C=O)C>[Br:1][C:2]1[C:6]([C:39]#[C:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:5][Se:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1c[se]cc1I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Brc1c[se]cc1C#Cc1ccccc1
Temperature: 70 °C
Yield: 54.3 %

Procedure:
To a pressure vessel purged with N2 was added 3-bromo-4-iodo-selenophene (1.97 g, 5.87 mmol), DMF (5.20 mL), triphenylphosphine (0.307 g, 1.17 mmol), copper(I) iodide (0.0740 g, 0.387 mmol), diethylamine (dried over KOH, 9.20 mL, 88.0 mmol), phenyl acetylene (0.645 mL, 5.87 mmol), and palladium dichloride-bis-triphenylphosphine (0.272 g, 0.387 mmol). The reaction vessel was sealed and the mixture heated to 70° C. for 1 h. Upon cooling to room temperature, the reaction mixture was diluted with MTBE (50.0 mL) and was washed with 0.1 M HCl (3×30.0 mL). The combined aqueous layers were extracted with MTBE (30.0 mL). The MTBE rich layer was dried over magnesium sulfate and concentrated to an oil. The crude oil was purified by column chromatography (silica gel, cyclohexane) to provide 3-bromo-4-phenylethynyl-selenophene (1.07 g, 3.19 mmol, 54.3 mol %): 500 MHz 1H NMR (CDCl3) δ 8.18 (d, J=2.9 Hz, 1H), 7.90 (d, J=2.9 Hz, 1H), 7.58-7.54 (m, 2H), 7.36-7.32 (m, 3H); 125 MHz 13C NMR (CDCl3) δ 134.2, 131.7, 128.5, 128.4, 126.8, 126.3, 122.9, 114.1, 91.0, 84.7.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[N:5][N:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[ClH:1].[CH:20]1([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8]([C:6]3[S:7][C:3]([CH2:2][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:4][N:5]=3)=[CH:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: COc1cccc2c(-c3nnc(CCl)s3)cn(CC3CCCCC3)c12
Solvent: C1CCOC1
Product: COc1cccc2c(-c3nnc(CN4CCCC4)s3)cn(CC3CCCCC3)c12
Product: Cl
Yield: 40 %

Procedure:
To a solution of 3-(5-chloromethyl-[1,3,4]thiadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (93 mg, 0.25 mmol) in tetrahydrofuran was added pyrrolidine (0.101 ml, 1.235 mmol) and the mixture subjected to microwave irradiation at 150° C. for 5 minutes. The resulting reaction mixture was purified by flash column chromatography to give the title compound (42 mg, 0.1 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (1M solution in diethyl ether; 1 ml, 1 mmol) was added. The excess reagent and solvent were removed in vacuo to afford the title compound as a 1:1 hydrochloride salt.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].CO>CCCCCCC>[CH3:24][N:23]([CH3:25])[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22]
Reactant: CN(C)C(=O)[C@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CN(C)C(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-N,N-dimethyl-benzeneacetamide hydrochloride (1:1) (CAN 129157-29-5) as starting materials. Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 394.2126 (M+H)+, αD20 (MeOH)=−44.9°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(#N)C.[Cl:10][CH2:11][C:12](Cl)=[O:13]>CO>[Cl:10][CH2:11][C:12]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: NCC(O)CO
Solvent: CO
Solvent: CC#N
Product: O=C(CCl)NCC(O)CO
Temperature: -10 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
3-Amino-1,2-propanediol (16.8 g, 184 mmol) was dissolved in MeOH (90 mL) at RT and the solution was diluted with ACN (acetonitrile) (550 mL) TEA (30.5 mL, 219 mmol) was added and the reaction mixture was cooled to −10° C. Chloroacetyl chloride (22.2 g, 15.6 mL, 197 mmol) was added dropwise at −10° C. for 2 h under nitrogen atmosphere and further maintained at −10° C. for 1 h and the reaction mixture was allowed to RT and stirred overnight (15 h). The solvents were removed under vacuo. The residue was purified by flash column chromatography (normal phase, gradient 1 percent to 20 percent MeOH in EtOAc) to afford the title compound (20 g) as a colorless oil m/z 168.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1)=[O:4].C(OCC)(=O)C>O1CCCC1>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][Br:1])[CH:13]=[CH:12][C:8]1=2
Reactant: O=C(CBr)c1ccc2sccc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccc2sccc2c1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A solution of 7.5 g of (+)-diisopinocamphenylchloroborane dissolved in 15 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 4 g of 5-bromoacetylbenzo[b]thiophene. The resulting mixture was stirred for 4 hours at -20° C. to -15° C. The reaction mixture was added to a mixture of 80 ml of ethyl acetate and 80 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure The residue thus obtained was purified by column chromatography (eluant: hexane:ethyl acetate=10:1) to obtain 3.8 of (R)-1-(benzo[b]thiophen-5-yl)-2-bromoethanol.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([NH:38][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CN
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 mg (1.05 mmol) of CDI were added to a solution of 323 mg (1.00 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (16 ml), and the mixture was stirred for 1 hour at RT. 99 μl (1.00 mmol) of isobutylamine were then added, and stirring was continued for a further 5 days at RT. The reaction solution was then washed in each case twice with a 4 M aq. ammonium chloride solution and a 1 M aq. sodium hydrogen carbonate solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was taken up in ethyl acetate (30 ml) and washed with 0.4 M hydrochloric acid (5 ml). The organic phase was again dried over MgSO4, filtered and concentrated in vacuo. 160 mg (0.42 mmol, 42 of N-(isobutyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue. MS: m/z 379.1 [M+H]+
Reaction SMILES: COC1C=CC(C[N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C@H:20]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)C(OCC2C=CC=CC=2)=O)=CC=1>CO.CC(O)=O.[Pd]>[NH2:8][C@H:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C@H:20]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CN3CCCC3)[C@H]2c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@H]1CC[C@H](CN2CCCC2)[C@H]1c1ccc(F)cc1
Yield: 77.6 %

Procedure:
A solution of 477 mg of product from Step D in 5 mL of methanol and 0.117 mL of HOAc was hydrogenated over 70 mg of 10% Pd/C at 40 psi for 18 h. The mixture was filtered and evaporated to afford 188 mg of oil. The residue was purified by flash chromatography eluting with 2 to 10% methanol in methylene chloride to obtain 108 mg of title compound. Mass spec (NH3 /CI): 263 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:17])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:9]2[C:10](=[O:16])/[C:11](=[CH:34]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)/[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)/C(=C/c2ccccn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a stirred solution of 2-(4-bromo-2,6-dichloro-phenyl)-3-methoxy-cyclopent-2-en-1-one (0.86 g, 2.56 mmol) in anhydrous tetrahydrofuran (17 ml) at 0°C. under an nitrogen atmosphere was added dropwise potassium hexamethyldisilazide (2.81 ml of a 1.0M solution in tetrahydrofuran, 2.81 mmol) over 10 minutes followed by dropwise addition of a solution of pyridine-2-carbaldehyde (0.268 ml, 2.81 mmol) in tetrahydrofuran (1 ml) over 5 minutes. The reaction was stirred at 0°C. for 10 minutes and then allowed to warm to room temperature over 1.5 hours. The reaction was quenched with saturated aqueous NH4Cl (25 ml) and extracted with EtOAc (3×25 ml). The combined organic extracts were washed with brine (15 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product (250 mg, 20%). 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (d, 1H), 7.70 (dd, 1H), 7.55 (s, 2H), 7.45 (d, 1H), 7.40 (s, 1H), 7.25-7.20 (m, 1H), 4.05 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[P:14]([O-])([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]>C(O)C>[NH2:5][CH:6]([P:14](=[O:15])([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CC(C)OP(=O)([O-])OC(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(C)OP(=O)(OC(C)C)C(N)c1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 186.5 %

Procedure:
To an ethanol solution (1.0 L) of ammonium acetate (37.6 g, 0.5 mol) was added molecular sieves (4 A) (10.0 g), benzaldehyde (53.0 g, 0.5 mol) and diisopropyl phosphate (6-a, 83.1 g, 0.5 mol) at room temperature. The reaction mixture was stirred at 60° C. for 2 days and cooled to room temperature. The reaction mixture was concentrated and ice-water was added. Then the mixture was acidified to pH approximately 1˜2 with concentrated HCl; and the solution was washed with Et2O to remove neutral materials. The aqueous phase was then basified to pH 11 with aq NaOH, and the product was extracted with DCM. Combined layers was washed with brine, dried over Na2SO4, and concentrated to give the title compound, 6-b, (253.0 g, 41%). LC-MS: (M+H)+ 272.
Reaction SMILES: Cl.N[OH:3].[OH-].[K+].[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.C1COCC1>[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14]([OH:3])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC(Cc1ccccc1)C(=O)Cl
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(Cc1ccccc1)C(=O)O

Procedure:
A solution of hydroxylamine hydrochloride (0.455 g, 6.55 mmole) in 25 ml of absolute methyl alcohol and a solution of potassium hydroxide (0.85 g, 12.8 mmole) in 25 ml of absolute methyl alcohol were cooled to 0° C. and mixed together. A solution of 2-benzylbut-3-eneoic acid chloride, prepared as described in A above, in 10 ml of dry THF was added at 0° C. to the mixed solutions with stirring. The cooling bath was removed and the mixture was stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 4.0 with 5% hydrochloric acid and the mixture was evaporated to remove methyl alcohol. The aqueous concentrate was saturated with sodium chloride and extracted four times with 75 ml portions of ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The 2-benzylbut-3-eneoic acid N-hydroxamide obtained as a pale brownish yellow oil was used without further purification in the following step.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)=O.C1(S(C2CCNC2)(=O)=[O:27])C=CC=CC=1.[CH2:34]([NH:36][CH2:37][CH2:38][NH2:39])[CH3:35]>>[CH2:34]([NH:36][CH2:37][CH2:38][NH:39][C:13]([N:12]1[CH2:14][CH2:15][CH:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:11]1)=[O:27])[CH3:35]
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Reactant: CCNCCN
Reactant: O=S(=O)(c1ccccc1)C1CCCNC1
Agent: O=C(Cl)Cl
Product: CCNCCNC(=O)N1CCC(S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound is prepared by reacting 3-(phenylsulfonyl)piperidine with phosgene and reacting the resulting 3-(phenylsulfonyl)pyrrolidine with N-ethylethylenediamine.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C[N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])(O)=O>ClCCl>[Cl:4][C:2]([CH2:1][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Solvent: ClCCl
Product: Cc1cn(CC(=O)Cl)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of 1-(carboxymethyl)thymine (9.2 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:5]1=[O:35])[CH2:2][CH3:3].Br[CH2:37][C:38]#[C:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:37][C:38]#[C:39][C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:5]1=[O:35])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(COCC[Si](C)(C)C)c1=O
Reactant: Cc1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4ccc(C)cc4)c3)n2COCC[Si](C)(C)C)n(COCC[Si](C)(C)C)c1=O
Temperature: 52.5 °C
Yield: 30 %

Procedure:
A mixture of 1-propyl-8-(1H-pyrazol-4-yl)-3,7-bis-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (prepared as per literature procedure US20080194593) (0.1 g, 0.18 mmol), 1-(3-bromo-prop-1-ynyl)-4-methyl-benzene (prepared according to example E1) (0.039 g, 0.18 mmol), potassium carbonate (0.051 g, 0.37 mmol), and acetone (10 ml) were heated at 50-55° C. for 16 hours. Reaction mixture was cooled to 20-25° C. and filtered off. The filtrate was evaporated and residue was purified by preparative TLC to afford 1-propyl-8-[1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazol-4-yl]-3,7-bis-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.035 g, 28%) as a brown sticky mass.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[Cl:19])[CH2:17][NH:18][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C(C)(C)C)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 2-tert-butyl-5-(5-(aminomethyl)-2-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-75, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL), and dry THF (5 mL) to afford 0.180 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.08 (s, 9H), 1.49 (s, 9H), 4.24 (d, J=4.5 Hz, 2H), 7.32 (dd, J=4.5 Hz, 3.6 Hz, 2H), 7.43 (s, 1H), 7.50 (s, 1H), 8.14 (d, J=4.5 Hz, 1H); MS (m/z): 365.20 (M+H)+.
Reaction SMILES: NCC1CC2CC(C2(C)C)C1C.[CH3:13][C:14]1([CH3:21])[C@H:19]([OH:20])[C:17](=[O:18])[O:16][CH2:15]1.CC1(C)C(O)C(=O)OC1>>[CH3:13][C:14]1([CH3:21])[C@@H:19]([OH:20])[C:17](=[O:18])[O:16][CH2:15]1
Reactant: CC1(C)COC(=O)[C@H]1O
Agent: CC1(C)COC(=O)C1O
Agent: CC1C(CN)CC2CC1C2(C)C
Product: CC1(C)COC(=O)[C@@H]1O

Procedure:
The optically active bases (+)- and (-)-3-aminomethylpinane prove astonishingly stable in the course of the various stages of the process. In none of them are measurable quantities of by-products produced, so that when recycling the (+)- or (-)-3-aminomethylpinane and L-pantolactone for re-use, neither the 3-aminomethylpinane nor the racemized pantolactone has to be subjected to special purification treatments. The optical purity of the D-pantolactone obtained in accordance with the process corresponds, within the limits of analytical error, to the data given in Example 3 for the product obtained from a first separation, even after the optically active base used, the racemized pantolactone left in each case, and the solvent used, have been recycled 20 times; this shows that special purification treatments are not necessary. The new process gives optically pure D-(-)-pantolactone in an overall yield of 90%, based on the DL-pantolactone employed.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=2[F:23])[NH2:19])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=2[F:23])[NH:19][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cc(N)ccc2F)cc1
Product: CCOC(=O)C(=CNc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1)C(=O)OCC
Yield: 60 %

Procedure:
5.12 g (60% yield) was prepared by the method of Example 19G from 5.5 g 3-(4-t-butyldimethylsilyloxymethylphenyl)-4-fluoroaniline and 3.5 ml diethyl ethoxymethylenemalonate. A pale yellow-green oil was obtained. NMR (CDCl3, 250 MHz): 8.5 (d, 1H, J=12 Hz), 7.5 (ABq, 4H), 7.2 (m, 3H), 4.8 (s, 2H), 4.25 (m, 4H), 1.35 (m, 6H), 1.0 (s, 9H), 0.1 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-bromobenzoic acid (500 mg, 2.49 mmol) in DCM (12 mL) was added morpholine (260 mg, 2.99 mmol), EDCI (1.43 g, 7.47 mmol) and HOBt (1.0 g, 7.47 mmol). The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with DCM. The organic layer was concentrated to give the desired (3-bromophenyl)(morpholino) methanone as a crude product which was used in next step without further purification. LCMS (m/z): 270.1/271.1 [M+H]+/[M+2H]+
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:18])=[CH:9][C:10]([CH3:17])=[C:11]([S:13](Cl)(=O)=O)[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C(O)C.Cl.O>[Zn].C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:18])=[CH:9][C:10]([CH3:17])=[C:11]([SH:13])[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1
Reactant: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.6 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer was placed 1.83 g (5 mmol) of 5-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-4-fluoro-2-methylbenzenesulfonyl chloride, followed by addition of 1.6 g (25 mmol) of zinc, 10 ml of ethanol and 10 ml of (100 mmol) of 18% hydrochloric acid. The mixture was stirred at room temperature for 15 minutes. Then, the mixture was refluxed with heating until the zinc powder was dissolved completely. The mixture was cooled to room temperature. Thereto were added 30 ml of water and 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Vacuum distillation was conducted to distil off ethyl acetate to obtain 1.5 g of a crystal. Yield: 100%
Reaction SMILES: [O:1](C)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].CC1CN2CCN1CC2.C(O)C.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[O-]S(C(F)(F)F)(=O)=O.[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH:40]2C>C(#N)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH2:40]2.[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22]
Reactant: CC1C[N+]2(C)CC[N+]1(C)CC2
Reactant: COS(=O)(=O)C(F)(F)F
Agent: CC1CN2CCN1CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCO
Product: C[N+]12CC[N+](C)(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl triflate (3.2 g, 19.5 mmol) was added dropwise to a cold (0 ° C) stirred solution of 2-methyl-1,4-diazabicyclo [2,2,2]octane (2.5 g, 20.0 mmol) in dry acetonitrile under an atmosphere of dry nitrogen. The mixture was stirred at 0° C. for 1 hour and then at 20° C. overnight. The orange solution obtained was treated dropwise with ethanol until precipitation of a white solid ceased; this solid was recovered by filtration, washed with ethanol, dried in vacuo at room temperature and shown by n.m.r. spectroscopy (1H and 19F) to be 1,2,4-trimethyl-1,4-diazoniabicyclo[2,2,2]octane ditriflate (0.45 g, 0.99 mmol, 5%). Removal of acetonitrile from the filtrate in vacuo left an orange oil (3.6 g, 12.4 mmol, 64%), shown by n.m.r. spectroscopy (1H and 19F) to be methyl-N-methyl-1,4-diazabicyclo [2,2,2]octane triflate.