Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20](=[O:22])[CH3:21])[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:22])[CH3:21])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 87.8 %

Procedure:
A solution or 1.00 g (3.37 mmoles) of benzyl 2(R)-benzyl-4-oxopentanoate (prepared as described in Preparation 19) in 10 ml of ethanol was stirred at room temperature for 3 hours in the presence of 100 mg of 10% w/w palladium-on-charcoal and under about 4 atmospheres of hydrogen. At the end of this time, the catalyst was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixture of hexane and diisopropyl ether, to give 610 mg (yield 88%) of the title compound as white crystals, melting at 71°-73° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:40])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[N:19]([CH:36]4[CH2:38][CH2:37]4)[C:18]=3[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC[C:50]([N:52]=[C:53]=[O:54])=[O:51]>C1COCC1>[CH:36]1([N:19]2[C:18]3[CH:39]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[C:15]([F:40])=[CH:16][C:17]=3[N:21]3[C:50](=[O:51])[NH:52][C:53](=[O:54])[CH:22]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=4)=[O:24])[CH:20]23)[CH2:37][CH2:38]1
Reactant: O=C=NC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)OCc2ccc([N+](=O)[O-])cc2)n3C2CC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)N2C(=O)NC(=O)C(C(=O)OCc4ccc([N+](=O)[O-])cc4)C2N3C2CC2)CC1
Reaction time: 20 h
Yield: 59.7 %

Procedure:
A solution of p-nitrobenzyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazole acetate (553 mg, 1 mmol) in THF (50 ml) is treated in succession at 0° with triethylamine (300 mg, 3 mmol) and chloroacetyl isocyanate (298 mg, 2.5 mmol). After stirring for 20 hours the solvent is distilled off and the residues is taken up in ethyl acetate and washed in succession with water (50 ml) and 10 percent sodium chloride solution (50 ml). The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is recrystallized from ethyl acetate. There are obtained 373 mg (59%) of p-nitrobenzyl 5-cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-7-[4-(tert-butoxycarbonyl)-1-piperazinyl]pyrimido[1,6-a]benzimidazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccccc1OC
Temperature: 95 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (1.50 g, 2.9527 mmol) in toluene (40 ml) were added tetrakistriphenylphosphine palladium (205 mg, 0.1774 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 4.58 ml), lithium chloride (300 mg, 7.0771 mmol) and ethanolic solution (7.2 ml) of 2-methoxybenzene boronic acid (1.34 g, 8.8186 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (1.34 g, 2.8755 mmol, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].O[CH:24]([C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH:24]([C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH3:25]
Reactant: COC(=O)C(C)Oc1cccc(C(C)O)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1cccc(C(C)Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1

Procedure:
Into 10 ml of anhydrous tetrahydrofuran were dissolved 0.3 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenol, 0.199 g of methyl 2-[3-(1-hydroxyethyl)phenoxy]propionate and 0.232 g of triphenylphosphine; 0.179 g of dilsopropyl azodicarboxylate was added dropwise under ice-cooling and stirring and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure; the obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-(1-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}ethyl)phenoxy]propionate [Compound 2-21].
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of (±)-6-bromo-4-((cis-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (0.30 g, 0.62 mmol) in DMF (0.5 mL), was added 1-cyanocyclopropanecarboxylic acid (0.073 g, 0.65 mmol), BOP (0.30 g, 0.68 mmol) and DIPEA (0.23 mL, 1.31 mmol). The mixture was stirred at rt for 2 h, quenched with water, stirred, filtered and rinsed with water. The brown solid was dried under vacuum to afford (±)-6-bromo-4-((cis-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 90% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.1 min (analytical HPLC Method J).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].FC(F)(F)C(O)=O.Cl>CN(C=O)C.CC#N.O>[Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2cc(Cl)c(Cl)cc2N1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Temperature: 0 °C
Yield: 83.3 %

Procedure:
A 1 L round-bottom flask was purged with argon and charged with sodium hydride (6.94 g of a 60% dispersion of NaH in mineral oil, 0.174 mol) and 60 mL of anhydrous DMF. This suspension was magnetically stirred and cooled to 0° C. in an ice-bath and then treated slowly with a suspension of 6,7-dichloro-2H-1,4-benzoxazin-3(4H)-one (22.2 g. 0.102 mol) in 140 mL of anhydrous DMF. The reaction mixture was maintained at 0° C. for one hour and then treated slowly with ethyl bromoacetate (29.4 mL, 0.265 mol) over a period of 5-10 minutes. This reaction mixture was maintained at 0° C. for thirty minutes, allowed to warm to room temperature, and then was maintained at room temperature for thirty minutes. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=6.2 min) was gone and that a new compound had formed (Rt=7.5 min). The reaction mixture was poured into 5.5 L of 5% aqueous HCl and the product precipitated immediately as a yellow solid. The suspension was stirred for 10 minutes and the solid was filtered off to give a yellow filter cake. The solid was rinsed with ice-cold ethanol (3×200 mL) and hexanes (3×200 mL) and then dried under high vacuum to give ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (26.0 g, 0.085 mol, 84%) as a white powder. MS (ES) m/e 304 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C(O)C.Cl>O>[CH:1]1([CH2:7][NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1ccc(NCC2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccc(NCC2CCCCC2)cc1

Procedure:
A 4 g. sample of ethyl 4-[(cyclohexyl)methylamino]hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)[C:18]2=[O:31])[CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)[C:18]2=[O:31])[CH2:3]1
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)c(F)c4)[C@H](F)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a stirring solution of 3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (60 mg, 0.14 mmol, diastereomeric mixture from step H) in 10 mL of DCM at −78° C. was added 2.5 mL of boron tribromide (2.5 mmole) and the mixture allowed to warm to rt and stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with saturated NaHCO3 solution. The mixture was then diluted with DCM and the organic layer was separated and evaporated under reduced pressure. The crude compound was purified by preparative HPLC to give 3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one (20 mg, 0.047 mmol, 34% yield) (diastereomeric pair). LCMS (Method Q) RT=1.17 min, m/z 419.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][C@H:31]([CH3:33])[NH:30][CH2:29][C@H:28]2[CH3:34])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:30]1[CH2:29][C@@H:28]([CH3:34])[N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:32][C@@H:31]1[CH3:33])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)/C=C/c2ccc(Cl)cc2NC(=O)OC(C)(C)C)[C@@H](C)CN1Cc1ccc(F)cc1
Yield: 83.7 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4-chlorophenyl)-acrylic acid (595 mg, 2.0 mmol) and (2R,5S)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00/71535) (445 mg, 2.0 mmol) were dissolved in CH2Cl2, combined with EDCl.HCl (384 mg, 2.0 mmol) and stirred for 3 hours at room temperature. The reaction mixture was purified via chromatography (SiO2, EtOAc/hexanes 2/8) to yield the title compound as colorless foam (840 mg, 81%).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:55][O:56][CH2:57][CH2:58][S:59]([NH2:62])(=[O:61])=[O:60]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:42][CH2:43][C:44]([F:48])([F:47])[CH2:45][CH2:46]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:62][S:59]([CH2:58][CH2:57][O:56][CH3:55])(=[O:61])=[O:60])=[O:36])[CH2:27][CH2:28]1
Reactant: COCCS(N)(=O)=O
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C)CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.162 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.72-8.57 (m, 1H), 7.68-7.55 (m, 1H), 6.63-6.51 (m, 1H), 3.94-3.70 (m, 6H), 3.31 (s, 3H), 2.08-1.75 (m, 7H), 1.68-1.58 (m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS (ES+) m/z 464.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)(=[O:30])=[O:29])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (5.80 g) in pyridine (100 mL) was added pyridine-2-sulfonyl chloride monohydrochloride (14.0 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (5.70 g, yield 65%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 420 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH:10]([CH:23]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][OH:26].Cl.CC([O-])=O.[Na+].O>CCO>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10](/[CH:23]=[N:25]\[OH:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(C=O)CN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC1CC(/C=N\O)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 136.7 %

Procedure:
To a mixture of 1-benzyl-5-((tert-butyldimethylsilyloxy)methyl)piperidine-3-carbaldehyde (3.39 g, 9.75 mmol) in EtOH (50 mL) was added an aqueous solution of NH2OH—HCl (3.75M, 3.12 mL, 11.7 mmol) followed by an aqueous solution of NaOAc (1.5M, 5.2 mL, 7.8 mmol). The reaction mixture was stirred at room temperature for 18 h. H2O (30 mL) was then added and the EtOH was partially removed in vacuo (˜40 mL). The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. The combined aqueous fractions were extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine and dried (MgSO4) and concentrated in vacuo to afford 3.31 g (94% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.35 (6 H, m), 3.58 (2 H, d, J=4.5 Hz), 3.43-3.54 (2 H, m), 3.03 (2 H, d, J=4.5 Hz), 2.57-2.68 (1 H, m) 1.90-2.01 (2 H, m), 1.80-1.89 (1 H, m), 1.65-1.77 (2 H, m), 0.93-1.01 (1 H, m). LCMS (+ESI, M+H+) m/z 249.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[N:62]=[CH:61][CH:60]=[CH:59][C:56]=2[C:57]#[N:58])=[CH:51][CH:50]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[C:56]([C:57]#[N:58])=[CH:59][CH:60]=[CH:61][N:62]=4)=[CH:51][CH:50]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: N#Cc1cccnc1-c1ccc(O)cc1
Product: N#Cc1cccnc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
Title compound 56 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 56A in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.86 (dd, J=4.76, 1.69 Hz, 1H), 8.34 (dd, J=7.82, 1.69 Hz, 1H), 8.01 (d, J=7.67 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 7.77 (d, J=7.98 Hz, 1H), 7.66 (d, J=7.36 Hz, 1H), 7.32-7.53 (m, 5H), 7.07 (d, J=8.9 Hz, 2H), 4.83 (s, 2H), 4.07 (t, J=6.14 Hz, 2H), 3.70-3.73 (m, 2H), 3.18-3.22 (m, 2H), 3.01-3.03 (m, 2H), 2.00-2.08 (m, 2H). ESI (+)/MS: 673 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])=[O:18].N1C=CC=CC=1.[NH:32]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH:41]=O)[C:35]=2[CH:34]=[CH:33]1>O1CCCC1>[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][CH2:33][NH:32]3)[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(Cc2cccc3c2CCN3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.92 g of sodium triacetoxyborohydride, 2.26 of 1-methanesulfonylpiperazine hydrochloride and 545 mg of pyridine are successively added to a solution of 1 g of indole-4-carboxaldehyde in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled to 15° C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×30 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate), so as to give 890 mg of 4-(4-methanesulfonylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]4=[N:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]6)[CH:28]=5)=[CH:25][CH:26]=[C:21]4[N:20]=[C:19]3[C:41]3[C:42]([NH2:47])=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:22]4=[N:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:38][CH2:37][S:36](=[O:39])(=[O:40])[CH2:35][CH2:34]6)[CH:28]=5)=[CH:25][CH:26]=[C:21]4[N:20]=[C:19]3[C:41]3[C:42]([NH2:47])=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCS(=O)(=O)CC6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCS(=O)(=O)CC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
tert-Butyl[1-(4-{2-(2-aminopyridin-3-yl)-5-[3-(1,1-dioxidothiomorpholin-4-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)cyclobutyl]carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (33.2 mg, 85.1%) as pale yellow solid.
Reaction SMILES: [C:1]([S:5][CH:6]1[N:9]([CH2:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8](=[O:21])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([S:5]([CH:6]1[N:9]([CH2:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8](=[O:21])[CH2:7]1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)SC1CC(=O)N1CC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Temperature: -50 °C
Reaction time: 3 h

Procedure:
4-tert-Butylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.6 g, 2 mmol) was dissolved in dry dichloromethane (30 ml) and the solution cooled to -50° C. A solution of m-CPBA (0.32 g, 2 mmol) in dry dichloromethane (20 ml) was added dropwise and the resulting mixture stirred for an additional 3 h. The mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with sodium hydrogen carbonate solution, dried (MgSO4) and evaporated to give a solid which was purified by flash hromatography using ethyl acetate/ether and ethyl acetate as the eluting solvents. Evaporation of the appropriate fractions gave the title compound as a colourless solid, 0.3 g, 48%, m.p. 79-81° C.