Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH:18]1[CH2:20][CH2:19]1)=[O:9]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (17.6 g, 75 mmol) in CH2Cl2 (180 mL) was added oxalyl chloride (7.0 mL, 83 mmol). DMF (8 drops) was added, and the mixture was stirred for 2 h at rt (gas evolution). The mixture was reduced under reduced pressure, and the crude residue was diluted with CH2Cl2 (530 mL). The mixture was cooled to 0° C., and a sol. of cyclopropylamine (5.8 mL, 83 mmol) in CH2Cl2 (45 mL) was added dropwise. The mixture was stirred for 10 min at 0° C., and was allowed to warm to rt. DIPEA (14.3 mL, 84 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was diluted with more CH2Cl2, and was washed with aq. 10% HCl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was triturated with hexane, filtered, and dried under high vacuum to yield the title compound (19.3 g, 94%). LC-MS: tR=0.84 min; ES+: 316.89.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9])(=[O:3])[CH3:2].[C:15]([NH:18]N)(=O)[CH3:16].[C:20]12[C:26](=CC=CC=1)[NH:25]C(=O)OC2=O>>[C:1]([NH:4][NH:5][C:6](=[O:14])[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][CH2:16][C:15]1[NH:18][CH2:20][CH2:26][N:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNC(=O)c1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=O)NN
Product: CC(=O)NNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
Anthranilic acid N′-acetylhydrazide (prepared from acetic hydrazide and isatoic anhydride using the method described in Example 44) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N′-acetyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzohydrazide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC.C1CCCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[S:16][CH2:17][CH2:18][O:15]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: C1CCCCC1
Product: Clc1ccc(C2(Cn3cncn3)OCCS2)cc1
Yield: 27.9 %

Procedure:
To a slurry of 44.3 g 1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone in 800 ml dry toluene and 400 ml 1-butanol was added 31.2 g 2-mercaptoethanol and 51.0 g p-toluenesulfonic acid. The mixture was refluxed under a Dean-Stark trap for 48 hours. On cooling, a white solid precipitated out, which was removed by filtration. The filtrate was evaporated, the residue dissolved in dichloromethane and washed twice with 10% aqueous sodium hydroxide and once with water. The organic layer was dried, filtered and evaporated to leave an oil which was taken up in cyclohexane. The cyclohexane was evaporated to azeotrope off any remaining 1-butanol, leaving an oily solid which was triturated with petroleum ether to give 15.7 g of product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].C(OC(=O)C)(=O)C.[PH2](O)=O.[CH:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23]>I.O>[CH3:1][C:2]1[NH:3][C:4]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(C)(C)C=O
Agent: I
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c(CC(C)(C)C)c1C
Temperature: 35 °C

Procedure:
2,4-Dimethyl-3 -acetyl-pyrrole (548 mg) was warmed to solution in a mixture of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid. The solution was cooled to 35° C. and 0.85 ml of pivalaldehyde were added. The solution was stirred for ten minutes, by which time the initially dark brown color had changed to yellow, then poured into 125 ml of water. The product separated as a colourless powder (769 mg, 93%), m.p. 156°-163 ° C. For analysis, it was recrystallized from ether-pentane, sublimed at 115° C. (10-4 mm), and again recrystallized by extraction into hexane (thimble) as long colourless plates, m.p. 166°-167° C. after changing to prisms below 130° C. Anal. Calc. for C13H21NO: C, 75.31; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.30; N, 6.58.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by either B or C, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: OO.[O:3]1CCOCC1.[F:9][C:10]1[C:18]([O:19][CH3:20])=[C:17]2[C:13]([C:14](=[O:22])C(=O)[NH:16]2)=[C:12]([CH3:23])[CH:11]=1.[OH-].[Na+]>O>[NH2:16][C:17]1[C:18]([O:19][CH3:20])=[C:10]([F:9])[CH:11]=[C:12]([CH3:23])[C:13]=1[C:14]([OH:22])=[O:3]
Reactant: C1COCCO1
Reactant: COc1c(F)cc(C)c2c1NC(=O)C2=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(F)cc(C)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, a solution of 30% aqueous hydrogen peroxide (6.3 ml, 61.5 mmol) diluted with water (8.2 ml) was added to a dioxane (50 ml) solution of 6-fluoro-7-methoxy-4-methyl-1H-indole-2,3-dione (I-28) (2.57 g), at the same temperature, a water (230 ml) solution of sodium hydroxide (6.15 g, 153.8 mmol) was dropwise added, taking 1 hour, followed by stirring for 4 hours with gradually heating up to room temperature. The reaction liquid was washed twice with chloroform, acetic acid was added to the aqueous layer followed by controlling at pH of 3 to 4 and extraction three times with ethyl acetate, the organic layer was washed twice with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform alone was concentrated under reduced pressure to obtain the entitled compound (1.54 g, 28% from I-30) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([CH:13]=[CH:14][N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([C:19]4[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=4)=[CH:14][N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: CN1CCCCC1=O
Reactant: COc1cc2c3c(ccn3CCC2)c1
Product: COc1cc2c3c(c1)c(C1=CCN(C)CC1)cn3CCC2

Procedure:
By a method similar to Preparation 11, using 8-methoxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (0.28 g, 1.5 mmol), and N-methylpiperidone (Aldrich, 0.68 g, 6.0 mmol) 0.12 g (27%) of title compound was obtained: 1H NMR (300 MHz, CDCl3): 2.18-22.24 (m, 2H), 2.77 (s, 3H), 2.89-2.97 (m, 4H), 3.21 (t, 2H, J=61 Hz), 3.68-3.49 (m, 2H), 3.85 (s, 3H), 4.10 (t, 2H, J=5.7 Hz), 6.02 (m, 1H), 6.65-6.66 (m, 1H), 7.04-7.06 (m, 2H); MS (ELECTROSPRAY): m/e 283.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=O)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>CCO>[CH3:38][C:28]1[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:13]([C:11]1[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][N:10]=1)=[O:15])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1ncc(-c2cccc(Cl)c2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ncc(-c2cccc(Cl)c2)o1
Reaction time: 64 h
Yield: 70.9 %

Procedure:
A mixture of the product from Step 79c (0.419 g, 1.66 mmol, 1.0 eq), (R)-(+)-3-aminoquinuclidine (0.221 g, 1.75 mmol, 1.05 eq) and EtOH (4.0 mL) is heated under reflux. After 64 h, the mixture is cooled and the contents are filtered through glass wool into p-toluenesulfonic acid monohydrate (0.315 g, 1.65 mmol, 1.0 eq). The resulting solid is filtered and dried in vacuity to afford the title compound (0.59 g, 65%). HRMS (FAB) calculated for C17H18ClN3O2+H1 332.1165, found 332.1180.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CC=CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CC=CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL). Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) and methanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and the reaction mixture was stirred at 35° C. for 4 h. N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonyl chloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirred overnight. TLC indicated complete conversion. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography, eluting with DCM, to afford the title compound as a clear oil (0.660 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:20])[CH2:17][CH2:18][NH2:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:20])[CH2:17][CH2:18][NH:19][S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])(=[O:32])=[O:31])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: C=C(CCN)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of [4-(3-amino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (120 mg, 0.398 mmol) in THF (4 mL) was cooled to 0° C. and the solid 2-chlorobenzene-1-sulfonyl chloride (168 mg, 0.796 mmol) was added followed by N,N-diisopropylethylamine (154 mg, 209 μL, 1.19 mmol). After stirring for 2 hours at 0° C., the cooling bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 15 hours, then diluted with water and brine. The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a viscous oil. Flash chromatography (40 g ISCO column, 100% hexanes ramped to 50% ethyl acetate in hexanes) provided {4-[3-(2-chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.04-8.07 (m, 1H), 7.74 (dd, J=9.00, 5.80 Hz, 1H), 7.62 (s, 1H), 7.49-7.54 (m, 2H), 7.40 (dd, J=7.65, 2.89 Hz, 1H), 7.32 (dd, J=11.20, 2.60 Hz, 1H), 7.19 (td, J=8.60, 2.40 Hz, 1H), 5.52 (q, J=1.40 Hz, 1H), 5.08-5.10 (m, 1H), 5.03 (t, J=6.40 Hz, 1H), 3.80 (s, 2H), 3.73 (s, 3H), 3.09-3.16 (m, 2H), 2.51 (t, J=7.00 Hz, 2H), 2.31 (s, 3H). MS cald. for C24H24ClFNO4S [(M+H)+] 476.1, obsd. 476.1.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1
Reactant: Clc1cc2ncccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
A mixture of 5,7-dichloro-1,6-napthyridine (1 eq, 1 wt), 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (1.1 eq, 1.28 wt), and diisopropylethylamine (2 eq, 1.75 vol) in NMP (6 vol) is stirred at 110±5° C. for 17 h. The solution is cooled to 70-75° C. and water (6 vol) added over 47 min at 65-75° C. The mixture is aged at 65-75° C. for 50 min, then cooled to 45° C. to give a slurry. The mixture is slowly cooled to 20-25° C. then aged for 2.25 h. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C. As the solid still contains significant NMP (16.2% w/w) it is reslurried in 1:1 v/v NMP/water (7.3 vol). The slurry is heated to 65° C. and stirred at 65-66° C. for 1 h. The slurry is cooled to 20-25° C. and aged for 3 days. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(C)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn2ccccc2c1C(=O)O
Temperature: 4 °C

Procedure:
To a solution of ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (5.6 g, 24 mmol) in methanol (40 mL, 1000 mmol) was added aqueous sodium hydroxide solution (5.0 mL, 8 M) and the mixture heated to 4° C. for 60 h. The reaction was allowed to cool, hydrochloric acid (5.0 mL, 12 M) and water (150 mL) was added to give a colorless precipitate. The solid was filtered, washed with water and dried in a vacuum oven to give crude 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid, 2.63 g. A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.0 g, 11 mmol), in Acetonitrile (120 mL) and water (60 mL) was degassed and [I,I-Bis(trifluoroacetoxy)iodo]benzene (2.90 g, 6.74 mmol) was added and the reaction heated under argon to 60 C for 15 min. Gave a clear solution. N-Bromosuccinimide (2.40 g, 13.5 mmol) was added and the solution was stirred at 60° C. for 30 minutes under an atmosphere of argon. The color turned dark. The reaction was heated for a further 30 min, allowed to cool, concentrated to remove acetonitrile and the aqueous extracted with EtOAc (3×50 ml). The organics were combined, washed with ascorbic acid solution, water, dried (MgSO4) and concentrated. The product was purified by column chromatography on silica gel eluting with DCM to 0.5% MeOH in DCM. The title compound was isolated as an off white solid, 0.56 g. LC/MS (FA) ES+ 210.9, 212.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:10]=O)[C:5]([F:16])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])/[CH:10]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]([F:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)[C@@H](C=O)Nc1nc(Cl)ncc1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a, (0.45 g, 1.84 mmol) in dichloromethane (9.0 mL) was added ethyl 2-triphenylphosphoranylideneacetate (0.96 g, 2.75 mmol). After allowing the reaction mixture to stir at room temperature overnight, approximately half of the solvent was removed under reduced pressure. The remaining crude mixture was purified by directly loading onto a silica gel column (0-100% EtOAc/hexanes) to afford 535 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.41 minutes (M+H) 316.32.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.CCN(CC)CC.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:19]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:7]1=[O:11])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NCc2cc(I)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)N1Cc2cc(I)ccc2C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-iodo-2,3-dihydroisoindol-1-one (3 g) in DMF (60 mL), were added N,N-dimethylaminopyridine (DMAP: 14 mg), Et3N (4.84 mL) and tert-butyl-diphenylsilyl chloride (9.0 mL). The mixture was stirred at 50° C. for 2 h. After cooling, saturated NaHCO3 aq. was added into the reaction mixture. Then it was extracted with EtOAc. The organic layer was washed with water and brine, then was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The trituration with Et2O followed by filtration gave compound aa2-1 (2.78 g) as a yellow amorphous solid.
Reaction SMILES: [I:1][CH3:2].[CH3:3][N:4]([CH2:6][CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](=[O:10])[CH3:9])[CH3:5]>C(OCC)(=O)C>[I-:1].[C:8]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][N+:4]([CH3:2])([CH3:5])[CH3:3])(=[O:10])[CH3:9]
Reactant: CC(=O)C(CC(C)C)CN(C)C
Reactant: CI
Solvent: CCOC(C)=O
Product: CC(=O)C(CC(C)C)C[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
Iodomethane (20 g, 140.94 mmol, 2.00 equiv) was added dropwise to a solution of 3-((dimethylamino)methyl)-5-methylhexan-2-one (12 g, 70.05 mmol, 1.00 equiv) and ethyl acetate (50 mL). The solution was stirred at ambient temperature for about 16 hours., and the resulting preciptant was collected by filtration to afford the title product (15 g, yield=68%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1(C(OC)=O)[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11].[Cl-].[Li+].CS(C)=O>O>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][CH:5]1[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11]
Reactant: COC(=O)C1(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)CC=CNC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3CC=CNC3=O)c(Cl)cc2F)c1=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of 202 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3-methoxycarbonyl-3,4-dihydro-1H-pyridin-2-one, 52 mg of lithium chloride, 2 ml of dimethyl sulfoxide and 10 μl of water was stirred at 120° C. for one hour. The reaction mixture was cooled to room temperature, and then water was poured therein and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 70 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3,4-dihydro-1H-pyridin-2-one.
Reaction SMILES: O=[C:2]1O[N:5]=[N+:4]2[CH2:7][CH2:8][CH2:9][CH:3]12.C(OCCOCC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#C.C(=O)=O>>[N:5]1[N:4]2[CH2:7][CH2:8][CH2:9][C:3]2=[CH:2][C:19]=1[C:18]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C1ON=[N+]2CCCC12
Reactant: C#CC(=O)OCC
Agent: CCOCCOCC
Agent: O=C=O
Product: CCOC(=O)c1cc2n(n1)CCC2
Temperature: 122.5 °C
Reaction time: 5 h

Procedure:
The 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (971 g, 7.70 mol, made as in example 2) and 1,2-diethoxyethane (DEE, 2913 mL) are charged to a multinecked 12 L round bottom flask, is equipped with a water cooled condenser, and purged with nitrogen. The stirred solution is heated to 120-125° C. under a nitrogen atmosphere and ethyl propiolate (971 g, 9.90 mol) is added dropwise over a period of 3 hours (carbon dioxide evolution). The reaction is held at 120-125° C. for about 5 hours until the conversion is >99% (<1% of residual 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide, by GC-MS analysis). The mixture is then concentrated under oil pump vacuum using a rotary evaporator with a bath temperature up to 70° C. to a residue. About 1.5 kg of toluene is then added to the residue and the mixture is concentrated once more. A dark oil is obtained [1218 g, 46.9% strength, (HPLC) in 41% (real yield of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.ClCCl>O>[CH3:15][S:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
In a dried reaction flask, butyl 4-aminopiperidine-1-carboxylate (2.0 g, 10.0 mmol), methanesulfonyl chloride (0.77 mL, 10 mmol), and DIEA (2.6 mL, 15 mmol) were added to dichloromethane (40 mL). The mixture was stirred under an ice-water bath for 2 hr. LC-MS showed that the product was formed and the reactants vanished. The solution was concentrated under reduced pressure to produce a yellow oil. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and was purified with silica-gel column chromatography (ethyl acetate:petroleum ether=1:2) to obtain a white solid (2.67 g) in 96.0% yield.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([OH:21])=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C=O)C>[C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([Cl:25])=[O:21])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(c1ccccc1)N1CC(C(=O)O)C(c2ccsc2)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CC(C(=O)Cl)C(c2ccsc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The product from step c) (1064 mg, 3.53 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. under N2 atmosphere and oxalyl chloride (1345 mg, 10.59 mmol) was added, followed by 2 drops of DMF. The reaction was stirred at 0° C. for 15 minutes and was allowed to come to room temperature. The reaction mixture was stirred for 1.5 hours and was evaporated to dryness to give the subtitle compound as a solid. MS calculated for C17H18ClNOS +H: 320, observed as methyl ester [dissolved in methanol]+H: 316.