Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC([N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[S:43][C:44](Br)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([S:39]([C:42]2[S:43][C:44]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N1CCNCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (example B.52) (206 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (145 mg, 50%). MS (ISP) 586.1 [(M+H)+]; mp 223° C.
Reaction SMILES: [C:1]1([O:11][CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)[C:10]2[CH2:9][CH2:8]C[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]1([OH:34])C2CCCCC=2C=CC=1>>[CH3:24][O:34][C:2]1[C:1]([O:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:8][CH2:9]2
Reactant: Oc1cccc2c1CCCC2
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCCC4)C2)cc1
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2

Procedure:
3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine, M.S. (C.I.) (M/Z): 308 [M+H]+, starting from 5,6,7,8-tetrahydro-1-naphthol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21]([OH:23])=O)=[CH:8][C:7]2=[O:24].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][C:28]=1[NH2:39]>>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:30]=[CH:29][C:28]=1[NH:39][C:21]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:24])[CH:8]=1)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=2[N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:23]
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3OC)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 2-methoxy-4-morpholin-4-yl-phenylamine (SALOR) as prepared in Example 12, yielding a yellow solid. (55 mg=38%), LCMS-m/z=510.5.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[OH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:23][N:22]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[C:3]([O:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:23][N:22]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])=[O:20])[CH2:17][CH2:18]1)(=[O:4])[NH2:5]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.5 h

Procedure:
1.43 ml of trichloroacetyl isocyanate were added, whilst ice-cooling, to a solution of 5.59 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 50 ml of dry methylene chloride, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 120 ml of methanol. This solution was then stirred at room temperature for 4.5 hours in the presence of 35 g of silica gel (Merck, silica gel 60, 230-400 mesh). The silica gel was removed by filtration and the filtrate was freed from the solvent. The residue was purified by column chromatography through silica gel, using a 8:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 5.76 g of the title compound as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][C:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:33][CH:32]=3)([OH:31])[CH2:30][CH2:29]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Product: OC1(Cc2ccc(F)cc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=436.5 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-fluoro-benzyl)-piperidin-4-ol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25]>>[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 46.9 %

Procedure:
3-[3-(4-Methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (87 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1, step 5 above. No solid precipitated out. The reaction solution was rotary evaporated and purified by flash chromatography and eluting with (dichloromethane: methanol 13/1, 10/1, 8/1) to give (70 mg, 47% yield) of 3-[1-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=3[C:22](O)=[O:23])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[O:29]=[C:28]1[CH:27]([N:26]2[C:22](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][C:13]=3[O:12][CH2:11][C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=4[CH:9]=3)[C:16]2=[O:18])[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc5c(F)cccc5s4)c3C2=O)C(=O)N1
Yield: 44.3 %

Procedure:
A mixture of 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid (1.2 g, 3.4 mmol), alpha-amino-glutarimide hydrochloride (0.58 g, 3.6 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-isoindole-1,3-dione as a white solid (0.66 g, 44% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.08 min (97.5%); mp, 264-266° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.54-2.95 (m, 2H, CHHCH2), 5.11 (dd, J=6, 12 Hz, 1H, CH), 5.73 (s, 2H, CH2), 7.18-7.88 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.95, 48.82, 65.85, 109.57, 109.81, 116.04, 116.91, 118.02, 119.02, 119.07, 120.37, 125.98, 126.08, 127.39, 127.65, 133.38, 137.02, 140.81, 141.98, 142.06, 154.81, 155.10, 158.41, 165.17, 166.71, 169.91, 172.78. Anal Calcd For C22H15N2O5SF: C, 60.27; H, 3.45; N, 6.39; S, 7.31; F, 4.33. Found: C, 60.40; H, 3.26; N, 6.29; S, 7.24; F, 4.32.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3]([C:9]([OH:11])=[O:10])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[ClH:19]>[Pd].C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[CH:2][CH:1]=2)[CH2:15][CH2:14]1.[ClH:8].[ClH:19]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1

Procedure:
Referencing scheme 1 below, the synthesis begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, 3-acetylpyridine (3) is first reacted with phenyl chloroformate at nitrogen position and then regioselectively alkylated using Grignard reagents and catalytic amounts of copper (I) iodide to obtain intermediate dihydropyridine. The dihydropyridine was further deprotected to obtain 3-acetyl-4-methyl-pyridine(4) (Tanis et al., 1996). Product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(4-methyl-pyridyl)-2-propene-1-one (5). Nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(4-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-4-methyl-pyridyl)-2-pyrimidine-amine (7). The first WBZ1 synthesis consists of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(4-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords the Gleevec analog WBZ1 (PCT publication WO2004108699).
Reaction SMILES: [IH:1].Cl[C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1>C(Cl)Cl>[I:1][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1
Reactant: I
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reaction time: 18 h
Yield: 85.8 %

Procedure:
Hydroiodic acid (57% in water, 9.68 mL, 73.41 mmol) was added portionwise to 2-chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 5) (1.38 g, 5.06 mmol) in DCM (30 mL) at 20° C. and the dark mixture was stirred for 18 hrs. The mixture was quenched by the addition of sat. aq. K2CO3 (care: gas evolved). After basification, satd. aq. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (D6) (1.58 g, 4.34 mmol, 85.7% yield) a yellow solid, containing about 20% of the reduced H-compound.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:12]1([C:18](=[C:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:18](=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Reaction time: 2.5 h
Yield: 71.2 %

Procedure:
The dianion of t-butyl acetoacetate (13 mL of 1M solution, 13 mmol; prepared as described in Example 6) was added to a solution of 4-cyclohexyl-5,5-bis(4-fluorophenyl)-2,4-pentadienal (3.75 g, 11 mmol) in tetrahydrofuran at -50° C. After stirring for 2.5 hours the solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 0.5% methanol in methylene chloride to give 4.0 g of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(2-hydroxyethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH. A second crop was obtained by filtration from the filtrate, dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.90 (s, 3 H), 3.19-3.30 (m, 2 H), 3.46-3.61 (m, 8 H), 4.14 (s, 2 H), 4.34 (t, J=6.53 Hz, 2 H), 4.60-4.64 (m, 1 H), 7.09-7.16 (m, 2 H), 7.23-7.29 (m, 1 H), 7.37-7.44 (m, 2 H), 8.11 (d, J=0.84 Hz, 1 H), 8.55 (d, J=1.54 Hz, 1 H), 10.35 (t, J=5.48 Hz, 1 H), 17.12 (s, 1 H); ES+ MS: 523 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[CH2:5].O([CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:5][CH2:16][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18]1)=[O:13]
Reactant: C=C(CN1CCOCC1)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN2CCOCC2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a stirred cold solution (0° C.) of 2-morpholin-4-ylmethyl-acrylic acid methyl ester (110 mg, 0.594 mmols) and N-(methoxylmethyl)-N-(trimethylsilylmethyl)-benzylamine (182 μl, 0.71 mmols) in dichloromethane (2 ml) was added slowly trifluoroacetic acid (9 μl, 0.12 mmols). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate to provide title compound as clear oil (86 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC)=O)[C:4](=O)[CH:5]=[C:6]2[CH2:10][N:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:15]=3)[C:8](=[O:21])[C:7]=12.Cl.P(Cl)(Cl)([Cl:31])=O>C1COCC1>[Cl:31][C:4]1[N:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:21])[N:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:15]=3)[CH2:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)n1c(C)c2c(cc1=O)CN(c1cnn(CC(F)(F)F)c1)C2=O
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 95 °C
Yield: 68.1 %

Procedure:
As shown in step 21-iv of Scheme 21, to a solution of Compound 2066 (614 mg, 1.58 mmol) in THF (10 mL) was added HCl (6 M, 10 mL) at rt. The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. To the residue was added phosphorus oxychloride (15 mL, 161 mmol) and the reaction mixture was heated at 95° C. for 3 hours under an atmosphere of nitrogen. After cooling and concentrating the mixture under reduced pressure, ice was added followed by the addition of EtOAc 30 minutes later. The aqueous layer was extracted with EtOAc and the combined organics washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether:EtOAc, 1:1) gave 6-chloro-4-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (Compound 2067, 356 mg, 68%) as a white solid: ESMS (M+H) 330.90.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([Cl:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:20][C:15]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ncccc1N1CCNCC1
Yield: 110.7 %

Procedure:
Stir 4-(2-chloro-pyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (2.00 g, 6.72 mmol) in DCM (50 mL) at room temperature, then add trifluoroacetic acid (5 mL). Stir the reaction for 2 hr. and remove solvents in vacuo, then form the free base using SCX-2® chromatography washing with methanol then eluting with around 3 M ammonia in methanol. Concentrate in vacuo to give 1-(2-chloro-pyridin-3-yl)-piperazine as a brown oil (1.47 g, 110% yield). MS (m/z): 198 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:13]=O.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:13][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CC(=O)NCc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chloro-3-formyl-benzyl)-acetamide (382 mg, 1.81 mmol) and cyclopropylamine (0.194 mL, 2.71 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (102 mg, 2.71 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. EtOAc (50 mL) was added, and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (371 mg, 81%). LC-MS: tR=0.53 min; ES+: 253.11.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: OCCBr
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Solvent: CO
Product: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) is washed with deionized water to remove color. A mixture of 225 gm D-mannose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 is treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction is monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction is complete after about four hours, and then allowed to cool to room temperature. The solution is filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate is stripped to an amber oil in a rotory evaporator.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:39])[CH2:6][O:7][C:8]2[CH:9]=[C:10]([S:14]([N:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])=[CH:20][C:19]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)=[CH:18]3)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:4][C:5](=[O:39])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:17]3[CH:18]=[C:19]([CH2:29][NH:30][CH3:31])[CH:20]=[C:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])(=[O:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 3a (122 mg, 0.22 mmol) was dissolved in 8 mL of dichloromethane. The reaction solution was cooled in an ice bath, and 2 mL of trifluoroacetic acid were dropwise added. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. 20 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product N-cyclopropyl-2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetamide 3 (80 mg, a colorless oil) in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Temperature: 30 °C
Yield: 100.6 %

Procedure:
The compound (16) (74.6 g), p-toluenesulfonic acid (2.24 g) and toluene (350 ml) were mixed, and the mixture was heated under reflux for 3 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (150 ml) were added and mixed to it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then, the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 69.7 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (17). The yield based on the compound (14) was 86.8%.