Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].O=[C:26]([CH3:31])[CH2:27][C:28]([NH2:30])=[O:29]>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:27]([C:28]([NH2:30])=[O:29])=[C:26]([CH3:31])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[C:10](=[S:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(N)=O
Solvent: C1CCOC1
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde (238.2 mg, 1.82 mmol) and 3-oxobutanamide (183 mg, 1.82 mmol) are dissolved in 5 ml THF. Ethyl polyphosphate (0.30 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, it is quenched with 10 ml of water and extracted with 10 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacuo. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH2:23]([NH:25][CH3:26])C.C=O.[C:29](O)(=O)[CH3:30]>>[CH2:29]([C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[CH2:23][NH:25][CH3:26])[CH3:30]
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Reactant: CC(=O)O
Reactant: CCNC
Agent: C=O
Product: CCc1oc2c(c1CNC)CCN(C(=O)CCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.400 g (1.345 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.14 ml (1.6 mmol) of N-Ethylmethylamine and 0.13 9 (1.6 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:22]([CH3:37])[C:23]([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]3)=[N:24][N:25]=1>>[ClH:16].[CH3:1][C:2]1[S:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][S:20][C:21]3[N:22]([CH3:37])[C:23]([C:26]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]5)=[N:24][N:25]=3)[CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cc1nc2cc3c(cc2s1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C)sc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepine (0.13 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (0.16 mmol) and was obtained as a colourless slightly hygroscopic solid (24 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[S:28])[CH:21]=1.[CH3:29]I>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:27]([S:28][CH3:29])[NH:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccnc1
Reactant: CI
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(Nc1cccnc1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then pyridin-3-yl isothiocyanate (0.663 g, 4.9 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 4 h, and then filtered. To the filtrate methyl iodide (0.315 ml, 5.1 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was taken up into ethyl acetate and water. The organic layer was washed with 1N aqueous HCl (2×). The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography using heptane/ethyl acetate 1:2 as eluent and recrystallisation in ethyl acetate to give 294 mg (16%) of the title compound. Mp 181-182° C. 1H NMR (300 MHz, CDCl3): δ=2.20 (s, 3H), 7.36 (dd, 1H), 7.54 (dm, 2H), 7.6 (m, 1H), 7.88 (dm, 2H), 8.55 (m, 2H), 9.85 (br s, 1H); EI SP/MS: 365 (M+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:20]([F:19])([F:39])[F:40])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(OC(F)F)cc1)c1ccccc1C(F)(F)F
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: FC(F)Oc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Yield: 111.6 %

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (1.12 g, 4.7 mmol) and 2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydrol (173) (3.0 g, 9.4 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was partially purified by flash column chromatography [SiO2; ethyl acetate-iso-hexane (10:90-+15:85)] to afford an amber gum (2.83 g) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:8]32)[O:3]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1/[CH:26]=[C:27]1\[C:28](=[O:39])[N:29]([C:36](Cl)=[O:37])[C:30]2[C:35]\1=[CH:34][CH:33]=[CH:32][CH:31]=2>N1C=CC=CC=1.C1COCC1>[CH3:15][C:12]1([CH3:14])[O:13][C@H:7]2[O:6][CH:5]([CH2:16][O:17][C:36]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)/[C:27](=[CH:26]/[C:21]4[NH:22][C:23]([CH3:25])=[CH:24][C:20]=4[CH3:19])/[C:28]3=[O:39])=[O:37])[C@@H:4]3[O:3][C:2]([CH3:18])([CH3:1])[O:10][C@@H:9]3[C@H:8]2[O:11]1
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC3O[C@@H]4OC(C)(C)O[C@@H]4[C@H]4OC(C)(C)O[C@@H]34)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1,2,3,4-di-O-isopropylidene-D-galactopyranose (650 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspension of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) at 0° C. The reaction mixture was then gradually warmed to room temperature, stirred for 4 h, and concentrated. The residue was triturated with water and washed with ether to give 170 mg (65%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (3aR,5aS,8aS,8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:49]>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[C:11](=[O:12])[N-:10][C:9](=[O:13])[O:8]4)=[CH:4][CH:3]=3)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.[Na+:49]
Reactant: Cc1cc(Cl)ccc1-c1cccc(C=O)c1
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (500 mg), 4′-chloro-2′-methylbiphenyl-3-carbaldehyde (668 mg), acetic acid (0.33 ml) and THF (40 ml) was stirred at room temperature for 24 hours. Sodium triacetoxyborohydride (767 mg) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The solvent was evaporated under a reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, the solvent was evaporated under a reduced pressure, toluene was added to the residue, and the solvent was again evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (1.47 ml) were added to the resulting pale yellow foamy substance (620 mg), followed by stirring at room temperature for 5 minutes. The solvent was evaporated under a reduced pressure, the residue was purified by an ODS column chromatography (water-acetonitrile) and made into a solid by adding diethyl ether. The solid was collected by filtration and then dried by heating under a reduced pressure to obtain sodium 2-(4-{[(4′-chloro-2′-methylbiphenyl-3-yl)methyl]amino}benzyl)3,5-dioxo-1,2,4-oxadiazolidin-4-ide (160 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:32][O:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1N(C)C(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)cc1N(C)C(C)=O
Yield: 92.3 %

Procedure:
A mixture of 0.070 g (0.36 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-methoxy-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 135 mg of N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 92%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].C[C:12](P(OC)(O)=O)([C:14]([O-:16])=[O:15])C.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH3:33])=[CH:28][CH:27]=1)[CH:23]([CH3:25])[CH3:24]>C1COCC1.[NH4+].[Cl-]>[CH3:1][O:16][C:14](=[O:15])[CH:12]=[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=1)[CH3:33]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C=C(C)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a chilled (0° C.) solution of lithium bis(trimethylsilyl)amide (1.0 M, 56 mL) was dropwise added a solution of trimethylphosphonoacetate, keeping the temperature below 10° C. The solution was then allowed to warm to room temperature and stirred for an additional five minutes after which a solution of p-isobutylacetophenone in THF (25 mL) was added in one portion. The solution was slowly heated to 65° C. and allowed to reflux for thirty hours. The solution was cooled to room temperature then diluted with a 10% NH4Cl solution (100 mL), and extracted with ethyl acetate (2×100 mL). The organic layers were combined and dried over MgSO4, filtered, and filtrate concentrated to a white solid which was recrystallized from hexane/ethyl acetate to give 5.93 grams of 3-(4-isobutylphenyl)but-2-enoic acid methyl ester intermediate (89.9% yield).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O>[CH3:17][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-p-tolyl-3-trifluoromethyl-pyridine (8.4 mmol) in H2SO4 (6 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture 60 minutes at room temperature. Pour the mixture onto ice-water (30 mL), extract with EtOAc, neutralize with 1 N NaOH, dry over Na2SO4, and concentrate under vacuum to obtain 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[SH:26])[CH3:14].O>CO>[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[S:26][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:14]
Reactant: ClCc1ccccn1
Reactant: CCn1c(S)nc2ccccc2c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 4 h
Yield: 48.3 %

Procedure:
7.0 ml of 28% methanolic solution of sodium methoxide and 2.82 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.56 g of 3-ethyl-2mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 4 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 2.47 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[CH:24]=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)n1
Temperature: 125 °C
Yield: 19.6 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (29.3 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 5.6 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 470.2 (M+H)+, Rt 0.83 min.
Reaction SMILES: [H-].[Na+].[H][H].[C:5]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].Cl[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.Cl>O1CCOCC1.O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][CH:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C:5]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:21][CH:22]=1)#[N:25]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: [H][H]
Reactant: N#Cc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.79 g (494 mmol) of sodium hydride are added in portions (caution: evolution of hydrogen) to a solution of 121.5 g (659 mmol) of diallyl malonate in 1.5 liters of dioxane at 0° C. The mixture is warmed to room temperature and then stirred at 40° C. for 1 hour. Subsequently, at 40° C., 50 g (0.329 mol) of 4-chloromethylbenzonitrile, dissolved in 500 ml of dioxane, are slowly added dropwise, and the reaction solution is then stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture is added to 1200 ml of water. Care must be taken during this that the pH is <7 (where appropriate, a few ml of 1 M hydrochloric acid are metered in to about pH 2). The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. Excess diallyl malonate is then removed by high vacuum distillation (boiling point: 57° C.; 0.074 mbar). The distillation residue is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 20:1). 67 g (0.22 mol, 67% of theory) of a colorless solid are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[CH:11]1C=CC=CC=1.C=O.Cl.N1CCCCC1>O.C(O)(=O)C>[C:1]([C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: c1ccccc1
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C(C#N)C(=O)OC(C)(C)C

Procedure:
41.6 g of phosphorus pentachloride was dispersed in 150 ml of ether and then, while stirring and cooling in an ice-water bath, there was added dropwise, from a dropping funnel, a solution of 17 g of cyanoacetic acid dissolved in 50 ml of ether. Directly after the completion of the dropwise addition, the ether and phosphorus oxychloride were driven off with an evaporator and 150 ml of tetrahydrofuran added to the residue. While stirring at 50° C., 15.6 g of t-butanol was added dropwise. Following the dropwise addition, the reaction was continued for 8 hours, after which the t-butyl cyanoacetate was obtained by distillation. A suspension of 19.8 g of the t-butyl cyanoacetate obtained, 110 ml of benzene, 4.2 g of paraformaldehyde, 1 g of piperidine hydrochloride and 1 g of glacial acetic acid was heated and water eliminated while refluxing. After water no longer was given off, the benzene was distilled off. The residue was cooled, after which it was dissolved in acetone and reprecipitated in water. The resinous material was collected by decanting, then redissolved in acetone and subjected to thermal decomposition and distillation under reduced pressure. t-Butyl α-cyanoacrylate was obtained. 5 g of the t-butyl α-cyanoacrylate obtained and 100 mg of azobisisobutyronitrile were dissolved in 50 ml of tetrahydrofuran, and polymerization carried out at 60° C. Poly-t-butyl α-cyanoacrylate was obtained. The molecular weight of the polymer obtained determined by gel permeation chromatography (GPC) was, by polystyrene conversion, a number average molecular weight of 32,000 and a weight average molecular weight of 98,000. The polymer obtained was irradiated with an electron beam, and the value of the main chain scission efficiency Gs calculated from the number average molecular weight determined by GPC was 3.8.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:11](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-:12].Cl>C(#N)C>[CH2:9]([O:8][C:6]([NH:3][C:2]1[S:1][N:12]=[N:11][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Nc1snnc1C(=O)OCC
Temperature: 19 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
A suspension of sodium thiocyanate (24.30 g, 0.30 mole) in acetonitrile (120 ml), maintained at 19° C., was treated dropwise over 22 minutes with a solution of ethyl chloroformate (28.7 ml, 0.30 mole) in acetonitrile (25 ml). The resultant mixture was stirred for 25 minutes at 20° C. and then ethyl diazoacetate (31.5 ml, 0.30 mole) was added. After stirring for 24 hours, 6.0 N hydrochloric acid (300 ml) was added with cooling. Acetonitrile solvent was removed in vacuo and the residual aqueous suspension was extracted several times with ether. Combined ether extracts were washed with water, dried (Na2SO4) and evaporated to leave 51.0 g of ethyl 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylate. This ester was hydrolyzed by refluxing for 6 hours in a mixture of ethanol (80 ml) and aqueous 6 N hydrochloric acid (400 ml) to yield the title acid; m.p. 179°-180° dec. after crystallization from nitromethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])NCC(=O)N)([CH3:4])([CH3:3])[CH3:2].[CH2:13](N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:13][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
Carbamoylmethyl-carbamic acid tert-butyl ester (8a; 0.84 g, 4.8 mmol) was dissolved in dichloromethane (10 mL), and added with triethylamine (1.0 mL, 7.2 mmol) and benzyl chloroformate (0.85 g, 0.75 mL, 5.0 mmol) at 0° C. After stirring for 5 min, 4-dimethylaminopyridine (DMAP; 0.32 g, 2.6 mmol) was added slowly with continuous stirring at 0° C. for 1 h. After the reaction is completed, dichloromethane (10 mL) and saturated Na2CO3 solution (10 mL) were added. The organic phase was washed by H2O (10 mL), 1N HCl (20 mL), H2O (20 mL) and saturated NaCl solution (20 mL) separately, and dried over MgSO4 and concentrated under reduced pressure to remove dichloromethane to obtain white solid product 12 (1.15 g; 95%). 1H-NMR (200 MHz) (CDCl3) δ: 7.30˜7.38 (m, 5H, ArH), 5.17 (s, 2H, CO2CH2Ph), 5.02 (br, s, 1H, NHBOC), 3.94 (d, 2H, Gly-H), 1.43 [s, 9H, CO2C(CH3)3]