Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][C:4]=1[N+:11]([O-])=O.[Na+].[CH3:15][S:16]([O-:18])=[O:17].O>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][C:4]=1[NH2:11]
Reactant: CS(=O)[O-]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CS(C)(=O)=O)cc1N
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl chloride (3.09 g, 15.3 mmol) in 75 mL of absolute ethanol was added methanesulphinic acid sodium salt (3.1 g, 30.7 mmol). The reaction was heated to 80° C. for 16 h. The reaction was cooled to room temperature and poured into water and the aqueous layer was extracted with ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent. The fractions containing the desired product were concentrated to dryness, then redisolved in absolute ethanol and 10% palladium on carbon (500 mg) was added and the reaction was placed on the Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight to give 2-(methyloxy)-5-[(methylsulfonyl)methyl]aniline (1.7 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 6.74 (d, J=8.2 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.52 (d, J=8.2, 2.2, 1H), 4.76 (s, 2H), 4.19 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cs1
Yield: 91.7 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (800 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (704 mg, yield 92%). melting point: 123-124° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:22])=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Cl:22][C:5]1[N:4]=[N:3][C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:9])[CH:6]=1
Reactant: COc1ccc(CNC(=O)c2cc(Cl)nnc2Cl)cc1OC
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2cc(Cl)nnc2N2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,6-dichloro-N-(3,4-dimethoxybenzyl)pyridazine-4-carboxamide (1-2, 0.100 g, 0.292 mmol, 1.0 equiv) in chloroform (0.97 mL) at 25° C. was added morpholine (0.0252 g, 0.292 mmol, 1.0 equiv) and the reaction mixture was stirred for 24 hours at 25° C. The reaction mixture was directly purified by normal phase column chromatography (15 to 100% EtOAc in hexanes) to give the product as a yellow solid. ESI+MS [M+H]+ C18H21ClN4O4: 393.2 found, 393.1 required.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.C1C=CC=CC=1.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH2:27]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCCCC(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.7 Parts 5-aminopentanoic acid and 22.8 parts p-toluenesulfonic acid monohydrate is suspended in 180 parts benzene and 32.4 parts benzyl alcohol is added. A continuous water separator is attached to the flask and the mixture stirred at vigorous reflux temperature for 16 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the residual oil shaken with n-hexane. The supernatant is discarded and the gummy product rubbed with ethyl ether causing crystallization to take place. The solid is separated, by filtration and washed with ethyl ether to afford the desired 5-aminopentanoic acid benzyl ester p-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:32][C:33]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:35]3[CH2:36][CH2:37][C:33]([CH3:38])([CH3:32])[CH2:34]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CC1(C)CCNC1
Reactant: COc1ccc(Cl)cc1-c1nn(CC(=O)O)cc1NC(=O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)N2CCC(C)(C)C2)cc1NC(=O)c1cnn2cccnc12

Procedure:
To 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid (31.9 mg, 0.075 mmol) in 1 mL DMF was added 3,3-dimethylpyrrolidine HCl (15 mg, 0.11 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol), then triethylamine (42 uL, 0.30 mmol) and the whole stirred 30 min. The crude mixture was purified by reverse phase HPLC and lyophilized to afford 28.9 mg (76%) as a colorless solid. LCMS (ESI) m+H=508.1. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.34 (d, J=6.9 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.30 (t, J=9.3 Hz, 2H), 5.09 (d, J=17.8 Hz, 2H), 3.85 (s, 3H), 3.62 (t, J=6.7 Hz, 1H), 3.43 (t, J=7.1 Hz, 1H), 3.29 (s, 1H), 3.12 (s, 1H), 1.74 (t, J=7.0 Hz, 1H), 1.63 (t, J=6.9 Hz, 1H), 1.08 (d, J=9.9 Hz, 6H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H](CO)O)O)O>>[CH2:2]([OH:1])[C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)C(O)[C@H](O)CO

Procedure:
Finally, by catalytic hydrogenation of this mixture of D-arabinose and D-lyxose, and still without separating the two principal components of the mixture, D-arabitol is obtained in the practically pure state since D-lyxitol is a synonym of D-arabitol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].C[O-].[Na+].[CH:14](OCC)=[O:15]>C(OCC)C>[OH:15][CH:14]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC=O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(C=CO)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
300 g (1.94 moles) of 4-chloroacetophenone are added dropwise to a suspension of 105 g (1.94 moles) of sodium methylate in 1.7 l of diethyl ether. 144 g (1.94 moles) of ethyl formate are added dropwise at room temperature, with cooling. The reaction mixture is stirred under reflux for 3 hours and cooled to room temperature and the precipitate is filtered off with suction. The precipitate is dissolved in water, the pH value is brought to 1-2 with dilute hydrochloric acid, the mixture is extracted with ethyl acetate and the organic phase is concentrated. 216 g (61% of theory) of 4-chlorophenyl hydroxyvinyl ketone of melting point 44° C. are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(N(C)C([C@@H]1C[C@@H](O)CN1)=O)CCCC=C>>[CH2:1]([N:8]([CH3:24])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Product: C=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Yield: 35 %

Procedure:
Compound 71a was synthesized from compound 70a as yellow oil in 35% yield, following the procedure as described for compound 49.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH:11]2[CH2:16][O:15][C:14]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[O:13][CH2:12]2)[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:25])C.[OH-].[Na+]>CO>[CH3:8][C:7]1[C:2]([CH2:1][OH:25])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:13][CH2:12]1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.92 h
Yield: 59.5 %

Procedure:
The 2,3-dimethyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridine 1-oxide (3.31 g, 10.7 mmol) obtained in the step (10b) was mixed with acetic anhydride (30 ml, 331 mmol). The mixture was stirred at 85° C. for 1 hour and 55 minutes. After cooled to a room temperature, the reaction mixture was concentrated. To the residue, methanol (50 ml) and a 5N aqueous sodium hydroxide solution (30 ml, 150 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was separated between water and ethyl acetate. The organic layer was washed twice with a 1N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the title compound (1.97 g, yield: 59.5%) as a brown oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/C=C/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.22 g (0.62 mmol) of methyl 9-(3-cyclopentoxy-4-methoxyphenyl)-2,4,6,8-E,E,E,E-nontetraenoate in 75 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 20.9 hours after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be analytically pure as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].Cl>C(O)C.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH:16]1([CH:15]=[C:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 100 °C
Yield: 98 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (950 mg, 1.69 mmol) in ethanol (10 mL), tetrahydrofuran (2 mL) and 10% aqueous sodium hydroxide solution (1.5 mL) was heated at 100° C. for 1 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (680 mg, 98%) as a solid which was used without further purification.
Reaction SMILES: CC1C=CC(N=C=O)=CC=1N=C=O.CC1C(N=C=O)=CC=CC=1N=C=O.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-])=O.[CH3:36][C:37]1([N:46]([C:70](N)=[O:71])[C:47](=[O:69])[N:48](C2(C)C=CC=CC2N=C=O)[C:49]2([CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]2[N:55]=[C:56]=[O:57])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]1[N:43]=[C:44]=[O:45]>C1(C)C=CC=CC=1>[C:30]1([NH:27][C:70]([N:46]([C:37]2([CH3:36])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]2[N:43]=[C:44]=[O:45])[C:47]([NH:48][C:49]2([CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]2[N:55]=[C:56]=[O:57])=[O:69])=[O:71])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC1(N(C(N)=O)C(=O)N(C2(C)C=CC=CC2N=C=O)C2(C)C=CC=CC2N=C=O)C=CC=CC1N=C=O
Agent: Cc1c(N=C=O)cccc1N=C=O
Agent: Cc1ccc(N=C=O)cc1N=C=O
Solvent: Cc1ccccc1
Product: CC1(NC(=O)N(C(=O)Nc2ccccc2)C2(C)C=CC=CC2N=C=O)C=CC=CC1N=C=O

Procedure:
About 522 parts by weight of an isomeric mixture of about 80 parts of 2,4-toluene diisocyanate and 20 parts of 2,6-toluene diisocyanate, about 25 parts of nitrobenzene and about 600 parts by volume of toluene are treated and worked up as described in Example 1. A polyisocyanate mixture which consists substantially of 2 mols of tris-(1-methyl-2-isocyanatophenyl)biuret and 1 mol of N-phenyl-N',N"-bis-(1-methyl-2-isocyanatophenyl)biuret is obtained in a yield of about 480 parts; NCO content about 22.9%.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:19])[CH:6]([NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH2:7]O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][O:18][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])=[N:9]1)=[O:19]
Reactant: COC(=O)C(CO)NC(=O)CCCCC(C)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: N#N
Agent: [OH-]
Product: COC(=O)C1COC(CCCCC(C)=O)=N1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-hydroxy-2-(6-oxo-heptanoylamino)-propionic acid methyl ester (1.50 g, 6.12 mmol) in dry and degassed THF (24 mL) was added at −10° C. to a solution of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.79 g, 7.31 mmol) in dry and degassed THF (24 mL) and the resulting suspension was stirred at 0° C. for 1.5 h. The reaction mixture was then stirred at reflux for 1 h. The mixture was then allowed to cool down to rt and filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a light yellow oil. TLC: rf (97:3 EA-MeOH)=0.37. LC-MS-conditions 02: tR=0.62 min [M+H]+=228.53.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:29]1[N:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2cc3n(c2c1)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100 mg, 0.38 mmol) and DIPEA (246.72 mg, 1.91 mmol) in i-PrOH (2 mL) was added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (172.50 mg, 0.76 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 to afford 1-(2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (120 mg, 69.67% yield) as a colorless oil. LC-MS MS (ESI) m/z 449.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.66 (s, 1H), 7.44-7.40 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.27-6.25 (m, 1H), 5.79-577 (m, 1H), 5.13-5.02 (m, 1H), 4.21-4.16 (m, 1H), 3.97-3.91 (m, 1H), 3.82-3.71 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.21-2.15 (m, 1H), 1.12-1.08 (m, 3H), 0.96-0.93 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH3:30])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N+:23]([CH:27]([CH3:29])[CH3:28])(C)[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.COS([O-])(=O)=O.[H-].[Li+].C(S)C>CN(C)C=O>[F:31][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH3:30])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:27]([CH3:28])[CH3:29])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)[N+]1(C)CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C)CC1
Agent: COS(=O)(=O)[O-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To mixture of 4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1-methyl-1H-indol-5-yloxy]-1-isopropyl-1-methyl-piperidinium as monomethylsulfate salt (120 mg, 0.2 mmol, 1.0 eq.), lithium hydride (5 mg, 0.5 mmol, 2.5 eq.) in N,N-dimethylformamide (0.5 mL) was added ethanethiol (0.05 mL, 0.6 mmol, 2.7 eq.). The reaction mixture was stirred 1 h at 100° C., cooled down to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate then filtered and concentrated in vacuo. The crude mixture was purified by column chromatography on silica eluting with DCM/2N NH3 in methanol 19/1 to yield 89 mg (96%) of the title compound as white foam. MS (m/e): 420.5 (MH+, 100%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:23]=3[N+:49]([O-])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1>[Pt].C(O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:23]=3[NH2:49])[O:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2[N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Yield: 112.1 %

Procedure:
Under a nitrogen atmosphere, toluene (2 L) was added to a Parr vessel containing 5% platinum on carbon (3.6 g). N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-diamine (36.85 g, 61.66 mmol) was added followed by ethanol (300 mL). The vessel was sealed, purged with hydrogen, and placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 18 hours at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 39.25 g of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6].Cl[CH2:17][C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]>CN(C)C=O>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:5](=[O:7])(=[O:6])[N:4]([CH3:3])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]
Reactant: COCCOC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
In a manner similar to Example 1B, 1.0 g. of 91% sodium hydride was added over a period of one hour to a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.6 g. (0.017 mole) of 2-methoxyethyl chloroacetate in 15 ml. of dimethylformamide at 35° C. The exothermic reaction (55° C.) was allowed to stir for 2 hours after the addition was complete, and was then quenched in 5% hydrochloric acid solution and the product extracted with methylene chloride. The residue, remaining after the solvent was removed, was dissolved in 10 ml. of warm dimethylformamide and added to 100 ml. of 2% hydrochloric acid. The cooled suspension was stirred for 30 minutes and filtered. Drying of the filtered material gave 1.12 g. (24%) of the product identical with that prepared in Example 1B.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:20][C:19]([CH3:28])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OCC(OC)=O)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N>>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[NH:7][C:8]([C:10]([C:13]3[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][C:19]([CH3:28])=[C:18]4[C:14]=3[CH:15]=[CH:16][NH:17]4)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: Cc1cc(OCC(=O)O)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate was fully deprotected using the same procedure as described in Example 24-B to give the title compound. 1H NMR (TFA salt, 400 MHz, MeOH-d4) δ ppm 8.06 (s, 1H) 7.79 (s, 2H) 7.31 (d, J=3.28 Hz, 1H) 6.92 (d, J=3.28 Hz, 1H) 6.70 (s, 1H) 4.49 (m, 2H) 2.50 (s, 3H) 2.30 (s, 3H). HRMS calcd. for C21H18N4O4 (M+H)+ 391.1401. found 391.1394.