Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC.[CH:4]([NH:7][C:8]([C:10]1([CH3:23])[C:15]2=[CH:16][CH:17]=[CH:18][N:14]2[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2[O:11]1)=O)([CH3:6])[CH3:5].O1C2C=CC=C[C:28]=2[N:27]([C:34](N)=O)[CH:26]=C1.Cl>>[CH3:26][N:27]([CH2:34][C:18]1[N:14]2[C:15]([C:10]([CH2:8][NH:7][CH:4]([CH3:6])[CH3:5])([CH3:23])[O:11][C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=32)=[CH:16][CH:17]=1)[CH3:28]
Reactant: NC(=O)N1C=COc2ccccc21
Reactant: CC(C)NC(=O)C1(C)Oc2ccccc2-n2cccc21
Agent: CNC
Agent: Cl
Product: CC(C)NCC1(C)Oc2ccccc2-n2c(CN(C)C)ccc21

Procedure:
Alternatively, the procedure of this Example is followed to prepare compounds of formula 3 in which R2 is CH2NR4R5 in which R4 and R5 are as defined herein and A is COOR6 or CONR4R5 in which R4, R5 or R6 are as defined herein. For example, by using dimethylamine (40% aqueous solution) as the base and N-isopropyl-4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxamide, described in Example 15, 1-[(dimethylamino)methyl]-N-isopropyl-4-methyl-4H-pyrrolo-2,1-c][1,4]benzoxazine-4-carboxamide, nmr (CDCl3) δ 1.02 and 1.16 (2 xd, J = 7Hz, 6H), 1.75 (s, 3H), 2.70 (d, J = 4Hz, 6H), is obtained. [The corresponding hydrochloric acid addition salt of the latter compound has m.p. 125° - 127° C). Reduction of the latter compound according to the procedure of Example 42 yields 1-[(dimethylamino)-methyl]-4-[(isopropylamino)methyl]-4-methyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[CH3:4][NH:6][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCN(CC)CC
Reactant: CCCCCCCC(=O)Cl
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)NC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 g (0.37 mol) of methylamine hydrochloride are dissolved in 125 mL of dichloromethane, and 115 mL of triethylamine are then added. At 0° C., 70 mL (0.41 mol) of octanoyl chloride are added slowly. The reaction mixture is stirred for 3 hours at room temperature. The mixture is filtered and 100 ml of water are then added to the filtrate. The organic phase is separated out by settling, dried over sodium sulfate and evaporated. 61 g of N-methyloctanamide are obtained in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:46]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:42]1[CH2:43][CH2:44][CH2:45][N:39]([CH3:38])[C:40](=[O:46])[CH2:41]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCCNCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1CCCN(C(=O)C[C@@H](Cc2cc(F)ccc2F)NC(=O)OC(C)(C)C)CC1=O

Procedure:
To a stirred mixture of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (40 mg), EDC (29 mg), and HOBT (21 mg) in dichloromethane was added triethylamine (0.042 mL) and hexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride (33 mg). The resultant mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified by preparative TLC (silica gel, 8% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to yield the title compound.
Reaction SMILES: C([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:36]([O:35][C:33]([CH2:32][O:31][C:27]1[C:23]2[CH2:24][CH2:25][CH2:26][CH:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:21][C:22]=2[CH:30]=[CH:29][CH:28]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)COc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1cccc2c1CCCC(NC[C@H](O)COc1ccccc1)C2
Yield: 80.8 %

Procedure:
A mixture of (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.55 g) and 10% Pd/C (50% wet, 150 mg) in methanol (6 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 4 hours and filtered. The filtrate was evaporated in vacuo and the residue was chromatographed (chloroform-ethanol) over silica gel (8 g) to afford (2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (365 mg) as a pale yellow solid. The solid (109 mg) was treated with 4N hydrogen chloride in ethyl acetate and powdered from ether to afford (2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (96 mg) as a colorless amorphous powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then 4-morpholinecarbonyl chloride (0.55 mL, 4.7 mmol) was added. After 15 minutes the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature for 2 days. The reaction mixture was diluted with water (30 mL) and the pH was adjusted to 11 with potassium carbonate. The resulting precipitate was isolated by filtration and then recrystallized from isopropanol/water to provide 0.61 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 128.9−129.7° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:11])[CH:3]=1.C1[CH2:16][O:15]CC1.[Li]C(C)(C)C.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Br:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=1)[C:16]([Cl:24])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: C1CCOC1
Reactant: CC(C)c1cc(Br)cc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: c1ccccc1
Product: CC(C)c1cc(Br)cc(C(=O)Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
1,3-Dibromo-5-isopropyl-benzene (1.57 g, 5.65 mmoles) was dissolved into anhydrous THF (50 mL) under nitrogen, and was chilled to −78° C. To this stirring solution was slowly (over 10 min) added t-BuLi (3.6 mL, 6.1 mmoles, 1.7M solution in pentane). After the addition was complete the mixture was allowed to stir at −78° C. for an additional 30 min. After this period CO2 was bubbled through the stirring solution and the temperature was allowed to warm to ambient temperature. CO2 bubbling was continued for 3 hours and afterwards the reaction was allowed to stir for an additional 6 hours. After this period 1H HCl (10 mL) was added and the mix was evaporated in vacuo (-THF). The resulting aqueous mixture was extracted with DCM (3×20 mL) and the organic layer was dried over anhydrous Na2SO4. Evaporation in vacuo yielded the crude carboxylic acid as a white solid. The crude acid (1.22 g, ˜5.0 mmoles) was dissolved into C6H6 (20 mL) and to this was added freshly distilled thionyl chloride (0.5 mL, 6.9 mmoles). This mixture was heated to reflux and stirred at this temperature for 16 hours. After this period the reaction mix was evaporated in vacuo to yield crude 3-bromo-5-isopropyl-benzoyl chloride (1.0 g, 68%—2 steps) as a yellow liquid. 1H-NMR (CDCl3): δ 8.08 (t, J=1.8 Hz, 1H), 7.89-7.87 (m, 1H), 7.68-7.66 (m, 1H), 2.98 (m, J=6.8 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nccc(N2CCc3ccccc32)n1
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol), indoline (0.45 ml, 4.0 mmol) and N,N-diisopropylethylamine (0.69 ml, 4.0 mmol) in n-butanol (20 ml) was heated at 100° C. for 18 hours. Silica (3 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-40% ethyl acetate/isohexane, to give the product as a colourless solid (460 mg, 50%). NMR (CDCl3): 3.2 (t, 2H), 4.0-4.1 (t, 2H), 6.5 (d, 1H), 7.0-7.1 (m, 1H) 7.2-7.3 (m, 2H), 8.2 (m, 1H), 8.3-8.4 (m, 1H); MS (MH+): 232.7.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][S:7]2(=[O:12])=[O:11].S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:2][CH2:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][S:7]2(=[O:12])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2CCO
Solvent: ClCCl
Product: Cl
Product: O=S1(=O)C[C@@H]2C[C@H]1CN2CCCl
Temperature: 20 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A mixture of (1S,4S)-5-(2-hydroxyethyl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (80 mg, 0.418 mmol) and thionyl chloride (0.153 mL, 2.092 mmol) in dichloromethane (2 mL) was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to provide the title compound (90 mg, 87% yield) as a yellow solid. LCMS: m/e 210.02 (M+H)+, 1.76 min (method 2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH:7][C:14](=[O:15])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN(CCN)CCN
Solvent: ClCCl
Product: CN(CCN)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.5 %

Procedure:
N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.O>C(#N)C>[Br:30][CH2:31][C:32]1[N:33]=[C:34]([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:12]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[O:13])=[O:7])=[CH:22][CH:23]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: BrCc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50 g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in refluxing acetonitrile (20 mL) was added a solution of 2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile (10 mL) over 25 mins. The reaction was cooled to room temperature and water (20 mL) was added. The mixture was extracted with DCM (3×30 mL) and the organic layers were combine and evaporated to leave a solid which was triturated with hot ethyl acetate to give 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide as a white solid (1.449 g, 61%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.73 (s, 2H), 5.30 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.81 (s, 1H), 7.90 (t, 1H) 7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 494, 496 Br pattern.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]1([CH:27]2[CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:36]([O:35][C:33]([CH:32]1[CH2:31][CH2:30][CH2:29][N:28]([C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH:27]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CCCNC1c1ccccc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1c1ccccc1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 2-phenylpiperidine-3-carboxylate (54529-38-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=500.2 [MH+].
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([S:20][CH2:21][C:22]([OH:24])=[O:23])(=O)[NH2:18]>CN(C=O)C>[C:10]1([C:8]2[N:18]=[C:17]([S:20][CH2:21][C:22]([OH:24])=[O:23])[O:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Reactant: NC(=O)SCC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
23 g. of 1,2-diphenyl-2-chloroethanone is heated together with 18 g. of the ethyl ester of carbamoylmercaptoacetic acid in 150 ml. of absolute DMF for 3 hours to 70°. Then, the DMF is removed, and the residue, containing the ethyl ester of N-(1,2-diphenyl-2-oxoethyl)-carbamoylmercaptoacetic acid, is refluxed for 5 hours with a mixture of 100 g. of POCl3 and 200 ml. of benzene. The mixture is then evaporated under reduced pressure and the residue is purified by chromatography on silica gel, thus obtaining the ethyl ester of 4,5-diphenyl-2-oxazolylmercaptoacetic acid, m.p. 54°-56°.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[I-:13].[C:16]([CH2:15][CH2:14][NH+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[CH:2]1[CH3:1])([OH:18])=[O:17]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: O=C(O)CCI
Product: CC1[NH+](CCC(=O)O)c2ccccc2C1(C)C
Product: [I-]
Temperature: 80 °C

Procedure:
A 2-necked 50 milliliter round-bottomed flask equipped with a magnetic stirring bar and an argon inlet was charged with re-distilled (pressure 2 mm Hg, temperature 45° C.) 2,3,3-trimethylindolenine (7.95 grams, 50.0 mmol) and 3-iodopropionic acid (2.00 grams, 10 mmol). The mixture was heated to 80° C. for 12 hours, during which time the product precipitated out of solution and formed a highly viscous medium. Upon cooling, the reaction mixture was extracted three times with 200 milliliter portions of diethyl ether to remove all of the unreacted starting material. The remaining crystalline solid was then dissolved in 10 milliliters of water, extracted three times with 50 milliliter portions of diethyl ether, and extracted three times with 25 milliliter portions of CHCl3. The aqueous layer was then removed and dried under vacuum (1.0 mm Hg) for 24 hours. The resulting amorphous solid was then recrystallized from toluene/CHCl3 mixtures to produce the N-(2-carboxyethyl)-2,3,3-trimethylindolinium iodide product as 3.0 grams of a yellow solid (83.5 percent yield). 1H and 13C NMR spectra indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].IC.[CH2:15](N(C(C)C)C(C)C)C>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:15])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=S(O)c1cc(F)c(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 2,4,5-trifluorobenzenesulfinic acid (34 g, 173 mmol), in DMF (200 mL), was added iodomethane (21.6 mL, 347 mmol), and N-ethyl-N-isopropylpropan-2-amine (60.5 mL, 347 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was concentrated and partitioned between water and ethyl acetate and extracted with CH2Cl2. The combined organic layers were concentrated and purified over silica gel (15-100% EtOAc in hexanes) to afford 1,2,4-trifluoro-5-(methylsulfonyl)benzene (25.8 g, 123 mmol, 71% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[C:18]([C:22]3[CH:23]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)[CH:19]=[CH:20][CH:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:42])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:33][CH:32]([C:24]1[CH:25]=[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:31]2=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][C:10]3[CH:11]=[CH:12][N+:13]([O-:42])=[CH:14][CH:15]=3)[CH:17]=2)[CH:23]=1)[CH3:34]
Reactant: CC(C)c1cc(-c2cccc(C(Cc3ccncc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(-c2cccc(C(Cc3cc[n+]([O-])cc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reaction time: 18 h

Procedure:
To a solution of Example 60 (100 mg, 0.22 mmol) in CH2Cl2/MeOH (1:1, 6 mL) was added MMPP (320 mg, 0.65 mmol). After 18 h, the resulting reaction mixture was diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with ethanol/ethyl acetate, 10:90 to 25:75) provided the title compound.
Reaction SMILES: [NH3:1].[C:2]1([CH3:27])[CH:7]=[CH:6][C:5]([C:8](=[O:26])/[CH:9]=[C:10](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:14][CH:13]=2)\[CH3:11])=[CH:4][CH:3]=1>CCO.CS(C)=O.CCOC(C)=O>[NH2:1][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:27])=[CH:3][CH:4]=1)=[O:26]
Reactant: N
Reactant: C/C(=C\C(=O)c1ccc(C)cc1)c1ccc(OCCCC(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(C(=O)CC(C)(N)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Ammonia was bubble into a solution of Intermediate 11D (1.34 mg, 0.64 mmol) in EtOH (20 mL) and DMSO (12 mL) for 10 min at 0° C. The reaction was stirred at rt overnight in a sealed pressure vessel. Analytical HPLC showed reaction to have progressed only ca. 10%. The mixture was cooled to −15° C., then ammonia was bubbled through for 7 min. The vessel was sealed and the reaction was stirred at rt overnight. Analytical HPLC showed the reaction to be ca. 25-30% complete. The mixture was diluted with EtOAc (75 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to provide Intermediate 11E (281 mg, 20%) as a light brown oil. LCMS Anal. Calc'd for C21H24F3NO2 379.42, found [M+H] 380.3.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18]O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][NH:1][C:2]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: OCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CNC(=O)N1CCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Imidazolidine-2,4-dione (1.0 g, 9.99 mmol), 3-benzyloxypropan-1-ol (1.9 ml, 12.0 mmol) and triphenylphosphine (3.1 g, 12.0 mmol) were stirred in methylene chloride (20 ml) and cooled to 0° C. Diisopropyl azodicarboxylate (2.36 μl, 12.0 mmol) in dichloromethane (5 ml) was slowly added and the mixture stirred at ambient temperature overnight. The mixture was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 3-(3-benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 53%, containing 7% w/w triphenylphosphine oxide) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:14]=[O:15].[ClH:16]>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:14](=[O:15])[C:11]=1[CH2:10][Cl:16])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=O
Reactant: Cl
Reactant: CC1=CC(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: CC1=C(CCl)C(=O)c2ccccc2C1=O
Yield: 55 %

Procedure:
A mixture of 17.2 g (0.1 mole) of 2-methyl-1,4-napthoquinone and 6 g (0.2 mole) of paraformaldehyde was heated to 60° C. in 50 mL of glacial acetic acid and stirred while dry HCl was bubbled through the solution for about 3 hrs. To the cooled mixture was added 200 mL of water, the solid was filtered and rinsed with 50 mL of water. It was then suspended in 200 mL of CH2Cl2, filtered, rinsed with CH2Cl2, and the filtrate was water washed, dried, and evaporated to leave 20.5 g of crude 2-methyl-3-chloromethyl-1,4-napthoquinone. The crude product was purified by sublimation at about 100° C. and pressure of 0.05 mm to give 12.7 g. Since there had been some splatter during the sublimation, the product was resublimed to give 12.1 g (55% yield), m.p. 102-104° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:8][CH2:9][CH3:10].CC(C)=O>C(N(CC)CC)C>[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:13]([Cl:15])([Cl:16])[Cl:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCSC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Reactant: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCSC(NC(=O)c1ccccc1OC(=O)OCC)C(Cl)(Cl)Cl
Yield: 78.3 %

Procedure:
13 g of ethyl chlorocarbonate was added to the mixture of 3.4 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide and 50 ml of acetone under stirring, and 1.0 g of triethylamine was added dropwise thereto at 0°-5° C. After effecting the reaction at room temperature for one hour, the solvent was distilled off under reduced pressure, 50 ml of water was added thereto and the solution was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to obtain 3.2 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-ethoxycarbonyloxybenzamide as a brown oily substance. nD25 1.5350