Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[C:22]([O:24][CH3:25])=[O:23].[BH4-].[Na+].Cl>CO>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flask, methanol (1.425 mL) and triethylamine (0.0277 g, 0.274 mmol) was added to 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.0587 g, 0.228 mmol). The reaction was allowed to stir at room temperature for 15 minutes. Sodium borohydride (0.0285 g, 0.753 mmol) was added to the flask one portion. The reaction was allowed to stir at room temperature for an additional hour. Using 1N hydrochloric acid, the reaction was neutralized to pH 7 and then concentrated under vacuo. Water (2 mL) was used to dissolve the residue. The mixture was extracted using dichloromethane (3×2 mL). The extracts were combined, washed with saturated sodium bicarbonate, dried using sodium sulfate, and concentrated under vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: C(Cl)[Cl:2].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(Cl)(Cl)(=O)=O>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:21])[CH:19]([Cl:2])[CH3:20])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: ClCCl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(Cl)C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a methylene chloride solution (20 mL) of 4.80 g (20 mmol) of p-(benzyloxy)propiophenone, 2.97 g (1.1 equivalents) of sulfuryl chloride was added at 15° C., followed by 16 hours of stirring. After 20 mL of water was added, methylene chloride was distilled off under a reduced pressure, and extraction was conducted by adding 40 mL of ethyl acetate. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. A colorless, oily substance (6.299 g) was thereby obtained. The oily substance was crystallized from 0.5 mL of ethyl acetate and 20 mL of hexane to obtain white crystals of 1-[4-(benzyloxy)phenyl]-2-chloro-1-propanone (4.3787 g, isolation yield: 75%).
Reaction SMILES: S(=O)(=O)=O.N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][OH:24])[CH2:21][O:20][C:19]1([CH3:26])[CH3:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CS(C)=O.C(N(C(C)C)CC)(C)C>[C:11]([O:15][C:16]([N:18]1[C@H:22]([CH:23]=[O:24])[CH2:21][O:20][C:19]1([CH3:26])[CH3:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Agent: O=S(=O)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
Add dropwise over 2 hours a solution of pyridine sulfur trioxide (390 g, 2452.83 mmol) in dimethylsulfoxide (1600 mL) to a 6° C. maintained solution of (S)-4-hydroxymethyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (350 g, 1515.15 mmol) in diisopropylethylamine (1225 mL) with a dimethylsulfide trap. Over 30 minutes add water (1050 mL) keeping temperature below 15° C. Stir at 15° C. for 1.5 hours under a stream of nitrogen. Extract with ethyl acetate (5 L), wash with 5%-aqueous citric acid (2×1.5 L), saturated aqueous sodium chloride (2×1.5 L), dry (magnesium sulfate), filter, and concentrate to give the desired compound which is used in the next reaction without further purification (365 g).
Reaction SMILES: [C:1]([C:4]1([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)(=[NH:3])[NH2:2].C[O-].[Na+].CN(C)/[CH:27]=[CH:28]/[CH:29]=O>CO>[CH3:19][C:18]([CH3:21])([S:16]([NH:15][C:4]1([C:1]2[N:2]=[CH:29][CH:28]=[CH:27][N:3]=2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:7]1)=[O:17])[CH3:20]
Reactant: CN(C)/C=C/C=O
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(C(=N)N)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(c2ncccn2)C1
Temperature: 70 °C
Yield: 11.3 %

Procedure:
To the above reaction mixture of tert-butyl 3-carbamimidoyl-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (assumed 4.98 mmol) in methanol (5 mL) was added sodium methoxide (0.509 g, 9.42 mmol) and (E)-3-(dimethylamino)acrylaldehyde (0.560 g, 5.65 mmol), and the resulting solution was heated at 70° C. overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The mixture was washed with water followed by saturated brine solution, and then dried over Na2SO4 and concentrated. The crude product was then purified by column chromatography (50% EtOAc in Hexane) to afford tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 200 mg (overall 12%). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J=4.8 Hz, 2H), 7.24 (m, 1H), 4.63-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 2H), 1.47 (s, 9H), 1.29 (s, 9H). LCMS: (ES+) m/z observed=255.2 (M+H)+ of 2-methyl-N-(3-(pyrimidin-2-yl)azetidin-3-yl)propane-2-sulfinamide.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][C:9]1=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:12]([CH2:11][C:9](=[CH2:10])[C:8]([OH:15])=[O:14])=[O:13])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: C=C1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(CC(=O)c1ccc(C)cc1)C(=O)O
Yield: 52.9 %

Procedure:
In 150 ml of methylene chloride were dissolved 35.0 g of toluene and 22.4 g of itaconic anhydride. To this was added gradually 50.0 g of anhydrous aluminum chloride under ice-cooling with stirring, and then the mixture was stirred at room temperature for 5 hours for proceeding the reaction. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into a mixture of 40 ml of conc. hydrochloric acid and 500 g of ice, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized from a mixture of hexane and ethyl acetate to give 21.6 g of 3-(4-methylbenzoyl)-2-methylenepropionic acid (a compound of formula II wherein X is CH3 and Y is H) (yield: 53%)
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13].Cl.[OH-].[Na+]>O.[Cl-].[Zn+2].[Cl-]>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[CH3:11])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: C=C(C)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(N)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A mixture of anthranilic acid (82 g, 0.6 mol), α-methylstyrene (168 mL, 1,28 mol), zinc chloride (82 g, 0.6 mol) and concentrated hydrochloric acid (100 mL) is heated to 120° C. for four hours. The mixture is cooled and diluted with water (100 mL). The pH is adjusted to approximately 4 using 50% sodium hydroxide. The resulting solids are collected, washed with water and then partitioned between methylene chloride and water. The pH is adjusted to 5–6 with dilute hydrochloric acid giving two clear phases. The organic phase is separated and then dried over anhydrous sodium sulfate. The methylene chloride is removed and the solid residue obtained is recrystallized from heptane/toluene giving the title intermediate compound as a white solid melting at 142–144° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 25 °C

Procedure:
2-chloro-3-nitropyridine (structure 1 as shown in Scheme 1) was dissolved in THF (10 mL/mmol) in a round bottom flask. Aniline (1.0 eq.) (structure 2 as shown in Scheme 1) and diisopropylethylamine (1.05 eq.) were added. The reaction mixture was heated to the appropriate temperature for 4 to 36 hours. After cooling to room temperature the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL/mmol) and washed with water and brine (20 mL/mmol respectively). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product (red to brown solid) was solidified with hexane/ethyl acetate and collected by filtration. The product was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH2:36](N)CC>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][CH2:2][CH3:36])=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: CCCN
Product: CCCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SCCC)nc32)C(O)C1O

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1 step c) and propylamine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH3:17])([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH3:5].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].C(Cl)CCl.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([CH2:1][NH:2][CH2:3][C:4]([CH3:17])([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH3:5])=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CNCC(C)(C)Oc1ccc(C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(C)(C)CNCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a stirred mixture of methyl 4-(1-methylamino-2-methyl-2-propoxy)benzoate (200 mg, 0.84 mmol), 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (268 mg, 0.84 mmol), 4-DMAP(125 mg, 1.0 mmol) in DMF(5 mL) was added EDC(220 mg, 1.14 mmol) at ambient temp. The resulting mixture was stirred for a further 10 hr at ambient temp. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated. The residual gum was triturated with CH2Cl2 and Et2O to give 200 mg (44.1%) methyl 4-[[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]methylamino]-2-methyl-2-propoxy]benzoate as a crystalline material. 1H-NMR (CDCl3) δ 1.36 and 1.31 (each s, 6H), 3.24–3.88 (series of s, 13 H), 6.65–8.20 (seris of m, 14H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][N:23]([CH2:25][CH3:26])[CH2:22][CH2:21][N:20]3C(OCC3C=CC=CC=3)=O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][N:23]([CH2:25][CH3:26])[CH2:22][CH2:21][NH:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CCN(C(=O)OCc2ccccc2)C(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCNC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
To benzyl 2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]-4-ethylpiperazine-1-carboxylate (20 mg) was added 4M HCl in dioxane (1 ml). The solvent was evaporated, 1-methyl-2-pyrrolidinone (1 ml), zinc bromide (10 mg) and 10% palladium on carbon (50 mg) added and the mixture stirred under hydrogen at RT for 72 hours. Evaporation to dryness and purification on a 10 g SCX2 column, eluting sequentially with ethyl acetate, MeOH and 1% ammonia/MeOH gave the title compound (9 mg, 60%) by precipitation from CH2Cl2 with isohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:30])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (678 mg), ethyl 2-bromopropionate (362 mg), and potassium carbonate (207 mg) in dry N,N-dimethyl formamide (2 ml) was stirred overnight at ambient temperature. The mixture was poured into water and extracted twice with ethyl acetate. The organic layers were washed with water, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to yield 2-(4-chlorophenyl)-6-[1-(ethoxycarbonyl)ethoxy]-4-methyl-2H-1,2,4-benzothiadiazine -3(4H)-one 1,1-dioxide (816 mg). (R,S mixture)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1.O.[NH2:12][NH2:13]>>[NH:12]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NN
Reactant: CNCc1ccc(Cl)nc1
Solvent: O
Product: CNCc1ccc(NN)nc1
Temperature: 150 °C
Reaction time: 12 h

Procedure:
1.0 g (6.4 mmol) 1-(6-chloropyridin-3-yl)-N-methylmethanamine [for preparation see EP 0 556 684-A1] are initially introduced into 1.5 ml (1.6 g, 31.9 mmol) hydrazine hydrate and the mixture is stirred at the boiling point at a bath temperature of 150° C. for 12 h. The cooled reaction solution is concentrated and the residue is dried in vacuo. 1.1 g of the title compound, which is employed without further purification, are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@@H:18]1[CH2:22][NH:21][CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.654 g, 3.0 mmol) in 1:1 (MeOH/CHCl3) (50 mL) were added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.750 g, 3.0 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (1.91 g, 9.0 mmol) was added and the solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil. (0.897 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:26])[CH3:25])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Yield: 13.4 %

Procedure:
To a solution of 6.6 ml (1 M in THF, 7 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 2.0 g (6 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in 10 ml of THF. The mixture was stirred for 1 h before 0.7 g of acetic anhydride was added and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 3:7] afforded 0.3 g (13%) of the title compound as a colorless oil. MS: 374.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc(F)ccc1F
Product: O=C(O)Cc1ccccc1Nc1cc(F)ccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,5-difluoroaniline to yield 2-[(2,5-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][OH:8].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[S:35]([CH2:2][CH2:3][N:4]([S:9][C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH:7]([S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])[OH:8])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCN(CCC(O)S(=O)(=O)c2ccc(C)cc2)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
N-(2-Hydroxyethyl)-N-tritylsulfenyl-3-amino-1-propanol (5.0 g, 12.64 mmol) is dissolved in pyridine (100 mL) and cooled to 0° C. p-Toluensufonylchloride (2.65 g, 13.9 mmol) is dissolve in CH2Cl2 (50 mL) and added to the reaction mixture at 0° C. via dropping funnel. The reaction is monitored by TLC to completion. The reaction mixture is concentrated in vacuo and the resultant residue is dissolved in EtOAc and washed with H2O (3×50 mL) and brine (2×50 mL). The EtOAc is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography using EtOAc/hexanes as eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:25])=[CH:23][C:18]=3[N:17]=[C:16]2[NH:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[O:48][CH3:49])[CH:40]=3)[N:35](COCC[Si](C)(C)C)[N:34]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl>C(O)C>[CH3:49][O:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][N:34]=[C:33]2[NH:32][C:16]1[N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]2)[C:19]2[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:25])=[CH:23][C:18]=2[N:17]=1
Reactant: COc1ccccc1-c1ccc2c(c1)c(Nc1nc3cc(C(=O)NC4CCCC4)ccc3n1C1CCC(O[Si](C)(C)C(C)(C)C)CC1)nn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccccc1-c1ccc2[nH]nc(Nc3nc4cc(C(=O)NC5CCCC5)ccc4n3[C@H]3CC[C@H](O)CC3)c2c1
Temperature: 78 °C

Procedure:
A mixture of 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-N-cyclopentyl-2-(5-(2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carboxamide (15 mg, 0.000018 mol), HCl (300 uL, 0.01 M) and ethanol (1.2 mL) was heated at reflux 78° C. for 2 hours. The mixture was concentrated and purified by HPLC. The product fractions were lyopholized to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[N:13]=[C:12]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][O:25][CH2:26]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>N1C=CC=CC=1.CN(C=O)C>[CH:23]12[N:22]([C:12]3[N:13]=[C:14]([N:16]4[CH2:17][CH2:18][S:19][CH2:20][CH2:21]4)[N:15]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)[N:11]=3)[CH:27]([CH2:28][CH2:29]1)[CH2:26][O:25][CH2:24]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3CCSCC3)nc(N3C4CCC3COC4)n2)cc1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nc(N3CCSCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A suspension of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.418 g, 1.01 mmol) in pyridine (3 ml) and DMF (6 ml) was prepared. Tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was then added and the off-white suspension was allowed to stir at room temperature for 16 hours, at which time the suspension was light yellow. The suspension was filtered, washing with methanol, and concentrated. LCMS indicated reaction had not gone to completion. The crude product was dissolved in DMF (6 ml) and pyridine (3 ml) and additional tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was added. The solution was allowed to stir at room temperature for 18 hours, then filtered. The precipitate was washed with methanol and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline (0.195 g, 50%) as a yellow solid. (M+H) 385.1.