Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.Cl>[F:18][C:4]([F:3])([F:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([OH:14])=[O:13])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:9][CH:10]=1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
A suspension of NaH (60% dispersion in mineral oil (2.3 g, 60 mmol)) in NMP (80 mL) was cooled to 0° C. under nitrogen. The reaction mixture was treated with a solution of ethyl 2-(4-(trifluoromethyl)phenyl)acetate (4.672 g, 20 mmol) in NMP (20 mL) in a dropwise fashion over 10 minutes (effervescence occurred), followed by bis(2-bromoethyl)ether (2.8 mL, 22 mmol). After 15 minutes, the reaction was warmed to 23° C. After 20 hours, the reaction was diluted with a 10% HCl solution (300 mL; slowly, a lot of effervescence was observed) and extracted with diethyl ether (2×300 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 25-50% EtOAc/hexane) affording 3.76 g of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carboxylic acid. MS m/e=275.1 (M+H)+.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([NH:48][CH3:49])[N:45]=[CH:44][N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH:48][CH3:49])[CH:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CNc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)ncn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-6-methylaminopyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([S:20]([N:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[C:5]=3[CH:10]=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.4 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.3 mmol) in anhydrous THF (5 mL) was added to a suspension of sodium hydride (234 mg, 5.83 mmol, 60% dispersion in mineral oil) in anhydrous THF (15 mL) at 0° C. The resulting mixture was stirred at 0° C. for 45 min, and benzenesulfonyl chloride (1.12 g, 6.36 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred at RT for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with cyclohexane affording 7-Benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (1.52 g, 87%). 1H NMR (400 MHz, CDCl3): δ 8.24 (2H, m), 7.76 (1H, d, J=4.0 Hz), 7.69 (1H, m), 7.58 (2H, m), 6.69 (1H, d, J=4.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:32](=[O:34])[CH3:33])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)nn1
Temperature: 120 °C

Procedure:
In a sealed tube, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-piperazin-1-yl}pyridazine (150 mg, 0.396 mmol), tributyl-(1-ethoxyvinyl)tin (157 mg 0.435 mmol), and Pd(PPh3)4 (23 mg, 0.020 mmol) in toluene (5 mL). Degas the mixture with N2 and seal the tube. Heat the solution at 120° C. overnight. Cool and filter through Celite. Wash the Celite bed with EtOAc (25 mL). Evaporate the solvent and dissolve the residue in 1N HCl and heat at 50° C. for 2 h. Cool and extract with CH2Cl2 (2×25 mL). Discard the extracts. Basify the aqueous phase with 10 N NaOH and extract with CH2Cl2 (2×25 mL). Combine the organic extracts and wash once with saturated aqueous KF solution (50 mL). Dry the organic extract and evaporate to yield the title compound. 1H NMR (CDCl3) δ 7.89 (d, 1H), 6.90 (d, 1H), 3.85 (t, 4H), 3.64-3.59 (m, 4H), 3.26 (s, 2H), 2.77 (s, 3H), 2.75-2.66 (m, 5H), 2.33-2.30 (m, 4H), 1.91-1.68 (m, 4H), 1.43-1.40 (m, 2H); LC-MS (M+1)387.11.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]1=[O:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]1=[O:10]
Reactant: Cn1ccc(C=O)cc1=O
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccn(C)c(=O)c1

Procedure:
N-Methyl-4-formyl-2-pyridone* (30.17 g), monoethyl malonate (38.15 g), pyridine (150 ml) and piperidine (3 ml) were stirred under reflux for 61/2 hours. The reaction mixture was evaporated under reduced pressure to afford a residue which was crystallised from aqueous isopropanol to give ethyl β-(N-methyl-2-oxo-4-pyridyl)acrylate as a pale yellow solid (18.44 g), m.p. 126°-7° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].FN[C@@H](CC1C=C(O)C(O)=CC=1)[C:23](O)=[O:24].C([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)=O.C(O)C>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][CH:23]=[O:24])[CH3:3]
Reactant: O=C(O)[C@H](Cc1ccc(O)c(O)c1)NF
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride 1 (Luxen, A., Perlmutter M., Bida, G. T., Van Moffaert, G., Cook, J. S., Satyamurthy, N., Phelps, M. E. and Barrio, J. R. (1990) Remote, semiautomated production of 6- 18F!fluoro-L-dopa for human studies with PET. Appl. Radiat. Isot. 41, 275) (5.3 g, 18.3 mmol) and sodium formate (1.44 g, 21.2 mmol) in formic acid (52 mL) cooled in an ice bath was added acetic anhydride (20 mL) and stirred at room temperature for 3 h. After addition of ethanol (40 mL) the mixture was stirred at room temperature for an additional 3 h and evaporated. The residue was dissolved in ethyl acetate, filtered and the insoluble material was washed with, ethyl acetate. The combined filtrates were washed successively with aqueous 10% HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to a yellow syrup. Crystallization of the syrup from ethyl acetate-petroleum ether give a white solid 2 (3.1 g, 61%); m.p. 102°-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:4][C:5]([CH3:18])=[C:6]([CH3:17])[C:7]=1[NH:8][CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH2:33]([O:35][CH2:36][C:37](Cl)=O)[CH3:34]>C(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]1[N:8]([CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:11])[CH3:12])[C:7]2[C:6]([CH3:17])=[C:5]([CH3:18])[N:4]=[C:3]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:2]=2[N:1]=1)[CH3:34]
Reactant: CCOCC(=O)Cl
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A solution of N-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (1.80 g, 5.23 mmol) in 50 mL of CH2Cl2 was cooled to 0° C., under N2, and treated with triethylamine (728 μL, 5.23 mmol) and ethoxyacetyl chloride (574 μL, 5.23 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The resulting syrup was taken up in 50 mL of EtOH and treated with 3 mL of triethylamine. The solution was heated to reflux for 4 d. The reaction mixture was then concentrated and redissolved in 50 mL of xylenes and treated with pyridinium hydrochloride (0.5 g) and the mixture was heated to reflux for 4 d. The reaction mixture was concentrated and taken up in 100 mL of EtOAc and washed with saturated NaHCO3 solution, H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated. The resulting syrup was purified by column chromatography (SiO2, 80% EtOAc/hexanes) to give N-{2-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (980 mg) as a mustard colored foam.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.CCOCC>C(O)C.C(OCC)(=O)C>[CH2:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])[CH3:2]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (4.74 g.) was refluxed in ethanol (175 ml.) for 60 minutes; the mixture was filtered and the filtrate evaporated to give an oil. Trituration with ethyl acetate gave a solid (354 mg.), which was discarded. The ethyl acetate solution was extracted with sodium bicarbonate solution; the aqueous layer was then acidified and extracted with ethyl acetate. On drying and evaporation this solution gave a gum (3.34 g.), which was redissolved in hot ethyl acetate. Addition of a fourfold volume of ether gave a solid, which was discarded. The filtrate was concentrated and set aside at 0°; a white solid (548 mg.) crystallised out, m.p. 160°-165° (decomp.), [α]D25 = 157° (c 0.7, tetrahydrofuran) λλmax (NaHCO3 solution) 237nm (ε = 12,800), 260nm (ε = 8,000), νmax (CHBr3) 1770 (β-lactam), 1720 (COOH), 1659 and 1678 cm-1 (CONH). N.M.R. spectrum (D2O, with sodium bicarbonate) -O-CH2.CH3 systems centred at 6.5 and 8.83τ. (Found: C, 50.6; H, 4.8; N, 7.1; S, 16.3. C16H18N2O5S 2 requires C, 50.2; H, 4.7; N, 7.4; S, 16.8%). RF = 1.5 (System C), 1.35 (System B).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].C([O:16][C:17](OC(OC(C)(C)C)=O)=[O:18])(C)(C)C.O.[C:28](O)([CH3:31])([CH3:30])[CH3:29]>>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[C:17]([OH:18])=[O:16])([O:9][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:8]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Aminocaproic acid (10 g, 76 mmo) was dissolved in tert-butylalcohol (100 ml), 5N NaOH (15 ml, 76 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Di-tert-butyl-dicarbonate (18.3 g, 83 mmol) dissolved in tert-butylalcohol (100 ml) was added thereto and stirred at room temperature for 24 hours. Then, water (100 ml) was added thereto and the mixture was concentrated under a reduced pressure, cooled to 0° C., and then, 2N H2SO4 was added thereto dropwise until pH of the mixture became 2. Thereafter, the resultant was extracted with ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated. The concentrate was purified using column chromatography (ethyl acetate:toluene:acetic acid=20:10:0.3) to obtain the title compound (17.9 g) as a white solid.
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.[Cl-].[Na+]>CS(C)=O.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:4][C:17]#[N:18])[CH3:16]
Reactant: COC(=O)C(C#N)C1(C)CCOc2ccc(F)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(CC#N)CCOc2ccc(F)cc21
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A mixture of 3.1 g (11.8 mmol) of cyano-(6-fluoro-4-methylchroman4-yl)acetic acid methyl ester and 2.47 g (42.4 mmol) of sodium chloride in 30 mL of wet DMSO was warmed to reflux. The reaction was monitored by TLC. After 4 hours, the reaction was cooled and diluted with water and extracted with diethyl ether. The combined organic layers were washed with four portions of water, brine, dried over magnesium sulfate, and concentrated in vacuo to afford 2.1 g (87%) of (6-fluoro-4-methylchroman-4-yl)acetonitrile as an oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([OH:34])=O)=[CH:23][CH:22]=1)([OH:19])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:34])=[CH:23][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)c2ccccc12
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c2ccccc12
Yield: 74.1 %

Procedure:
Using General Procedure A with 200 mg (0.82 mmol) D-Proline benzyl ester hydrochloride and 100 mg (0.41 mmol) (4-carboxymethyl-naphthalen-1-yl)-acetic acid afforded, after flash chromatography (EtOAc), 188 mg (75%) of the title compound as a colorless oil. MS m/e (%): 636 (M+NH4+, 100), 619 (M+H+, 75).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][CH:26]([CH2:28][C:29](O)=O)[CH3:27].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O=P(Cl)(Cl)Cl>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:29]([CH2:28][CH:26]([CH3:27])[CH3:25])=[N:14][N:13]=3)[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Reactant: CC(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(CC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
In a 150 mL RBF was weighed 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.16 g, 2.55 mmol) followed by THF (20 mL), isovalerianic acid (0.29 mL, 2.55 mmol) (TCI America) and N-ethyl-N-isopropylpropan-2-amine (1.11 mL, 6.37 mmol). To this stirring suspension was added HATU (1.07 g, 2.80 mmol) in one portion and the solution was stirred at RT for 2 h. The mixture was concentrated and treated with POCl3 (10 mL, 107 mmol) under argon. The flask was fitted with a reflux condenser and the reaction was heated to 110° C. for 14 h. The excess POCl3 was removed under reduced pressure and the crude residue was treated with EtOAc and a saturated solution of NaHCO3. It was extracted with EtOAc (50 mL) and washed with brine and dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (0-50% EtOAc in Hex) affording 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-isobutyl-1,3,4-oxadiazole (277 mg, 35%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 522.0 (M+H)1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.97 (m, J=8.2 Hz, 2H), 7.87 (s, 1H), 7.43 (m, J=8.2 Hz, 2H), 2.84 (d, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.15 (dt, J=13.5, 6.8 Hz, 1H), 0.99 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.S(OC)(O[CH3:29])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:29])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 90°-93° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.CO[Si](C)(C)C.F[C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: CO[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 6-aminoisoquinolin-1-ol in DMF was added methoxytrimethylsilane and (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate and the solution was stirred at room temperature for 6 h. The mixture was poured into EtOAc, washed with NH4Cl(sat)/HCl (1N) followed by NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate) (91.8% ee by Chiracel OD-RH).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].CN(C)P(N(C)C)N(C)C>>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Agent: CN(C)P(N(C)C)N(C)C
Product: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Tert-butyl acrylate (465 g, 3.628 mol) was warmed to 100° C. under nitrogen, then hexamethylphosphorous triamide (10 g, 61.2 mmol) was added dropwise and the addition rate was adjusted to maintain the reaction temperature at 100° C. The reaction mixture was allowed to cool, then poured over a plug of silica (˜1000 ml) and washed completely off the silica with 4:1 hexane/ethyl acetate. The solvent was removed under reduced pressure and the resulting oil was distilled. Some material was collected from room temperature to 50° C. under high vacuum, and discarded. The temperature was then raised to ˜80° C. and the product (300 g, 65%, b.p. 67-70° C. at 300 μ) was collected as a clear oil. 1H NMR (CDCl3): δ 1.4 (m, 18H), 2.4 (t, 2H), 2.6 (t, 2H), 5.5 (s, 1H), 6.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][C:10](=O)NC2=[CH:5][CH:4]=1.[CH3:13]I.[CH3:15][N:16]([CH:18]=[O:19])[CH3:17]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:10])([CH3:13])[C:18](=[O:19])[N:16]([CH3:17])[C:15]2=[CH:5][CH:4]=1
Reactant: COc1ccc2c(n1)CC(=O)N2
Reactant: CI
Reactant: CN(C)C=O
Product: COc1ccc2c(n1)C(C)(C)C(=O)N2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.2 g (1.22 mmol) 5-methoxy-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (J. Het. Chem. 1996, 33, 287–93) was dissolved in 10 ml of DMF and cooled to 0° C. under a nitrogen atmosphere in a flame dried round bottom flask. To this solution was added 4.02 ml (4.02 mmol) of a 1M solution of potassium t-butoxide in THF and the solution was stirred for 10 minutes. To this solution was added dropwise 0.3 ml (4.88 mmol) of MeI, and the reaction was stirred for 15 minutes at 0° C. The reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on 6 g of silica using 3:1 hexanes/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.14 g of 5-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one. 1H NMR (CDCl3) δ 7.02 (d, 1H), 6.58 (d, 1H), 3.90 (s, 3H), 3.18 (s, 3H), 1.38 (s, 6H). Mass spectrum: m/e=207 (P+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>C1C=CC=CC=1>[CH3:1][N:2]([Si:15]([CH3:18])([CH3:17])[CH3:14])[CH2:3][CH2:4][N:5]([CH3:6])[Si:15]([CH3:18])([CH3:17])[CH3:14]
Reactant: CNCCNC
Reactant: C[Si](C)(C)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCN(C)[Si](C)(C)C)[Si](C)(C)C
Reaction time: 3.5 h

Procedure:
A mixture of 176 parts by weight of N,N'-dimethylethylenediamine, 1000 parts by volume of benzene and 552 parts by volume of triethylamine were stirred at room temperature and at the same time 434 parts by weight of trimethylchlorosilane, diluted with 500 parts by volume of benzene, were added dropwise over the course of 3 hours. The mixture was stirred for a further 3.5 hours and left to stand overnight, and the precipitate present was filtered off and washed with benzene. The combined filtrates were concentrated in a rotary evaporator and the residue was distilled in vacuo.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was partitioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400MHz) δ 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H) , 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.