Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:35]([O-])=O)[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6]>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:15])[F:16])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of 200 mg (0.4 mmol) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile and 375 mg (6.7 mmol) of iron powder in 4 mL of ethanol and 2 mL of acetic acid was warmed at 90° C. After 2 hours, the mixture was cooled and diluted with 50 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with three portions of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo to afford 130 mg (68%) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:27][CH2:26][CH2:25][C@@:19]3([CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:27][CH2:26][CH2:25][C@@:19]3([CH2:23][C:22](=[O:24])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@@H](O)C3)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CCC(=O)C3)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of (3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (195 mg) obtained in Step 9 of Example 104 in chloroform (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane; 259 mg) under ice-cooling, followed by stirring the mixture under ice-cooling for 3 hours and then at room temperature for 1 hour. To the reaction mixture was added aqueous sodium sulfite solution, followed by extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:6 to 1:4) to give (3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (190 mg).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:36])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:37])=O)(C)(C)C.[ClH:38].O1CCOCC1>C(#N)C>[ClH:38].[NH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:31][CH2:32]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:36])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:37]
Reactant: Cc1c(-c2ccc3c(c2)NC(=O)C(NC(=O)OC(C)(C)C)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(N)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 4 h

Procedure:
8-(3-(tert-Butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (29 mg, 0.046 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed. The solvents were evaporated and the crude was triturated with diethyl ether (4 mL) to afford the title compound EXAMPLE 50 as a yellow solid (20 mg, 98%). ESI-MS m/z: 404 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH:11]([CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](O)=[O:13].Cl.[CH3:44][O:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[OH:10][CH:11]([C:12]([NH:46][O:45][CH3:44])=[O:13])[CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Reactant: CON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
DIPEA (200 μl, 0.567 mmol) was added to a suspension of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (250 mg, 0.544 mmol) and O-methylhydroxylamine hydrochloride (90 mg, 1.078 mmol) in dichloromethane (50 ml) at 5° C. After about 5 min 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (665 mg, 1.748 mmol) was added, the pH adjusted to 8 via addition of further DIPEA, and the mixture then stirred for 1 h at 5° C. and then overnight at room temperature. Then dichloromethane (50 ml) was added, washed 2× with 10 ml of water and brine, dried, filtered and concentrated to give 430 mg of the crude product which was purified by chromatography on silica gel (dichloromethane+11-12% methanol. Concentration of the combined fractions and drying afforded 224 mg of a white amorphous solid;
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>O>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCCN(Cc2ccccc2)CC1
Agent: Br
Solvent: O
Product: c1ccc(CN2CCCNCC2)cc1
Temperature: 100 °C
Yield: 89.2 %

Procedure:
A mixture of 0.85 g of ethyl 4-benzylhomopiperazine-1-carboxylate and 5 ml of 47% hydrobromic acid was heated at 100° C. for 10 hours. After addition of a small amount of water, the reaction mixture was washed with ethyl acetate. The aqueous layer was made alkaline with 30% sodium hydroxide and, after salting out with sodium chloride, extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.55 g of 1-benzylhomopiperazine.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-])=O)C.N[C:21]1C=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=C[C:22]=1NCC>[Ni]>[CH3:21][CH2:22][NH:17][C:5]1[C:4]([NH2:3])=[CH:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[CH:7][CH:6]=1
Reactant: CCNc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Ni]
Product: CCNc1ccc(N2CCN(C)CC2)cc1N
Yield: 90 %

Procedure:
N-Ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was reduced with Raney-Ni as described previously for the synthesis of tert-butyl 4-[4-amino-3-(ethylamino)phenyl]-1-piperazinecarboxylate to give N-2-ethyl-4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (yield>90%) as a red oil. The product is very sensitive to oxidation and was therefore used immediately in the next reaction step. HPLC purity>90%; MS (posEI) m/z=234 (M+);
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:11].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][C:2]1[C:3]([C:8]([NH2:9])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccnc1C(N)=O
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 97 %

Procedure:
A mixture of 3-methylpicolinonitrile (2.36 g, 20 mmol) and conc. sulfuric acid (12.5 mL) was stirred at 80° C. for 25 min. The solution was cooled to rt, poured into water (80 mL), followed by addition of sat. Na2CO3 (aq.) until pH ˜7. The resulting mixture was extracted with DCM (3×) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to provide 3-methylpicolinamide as a white solid (2.65 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.43 (dd, 1H), 7.93 (brs, 1H), 7.62 (dd, 1H), 7.35 (dd, 1H), 5.44 (brs, 1H), 2.76 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][C:11]([CH2:15][C:16]([O:18]CC)=O)=[CH:12][C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[CH:22][N:23]=[C:3]12.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([NH:31][C:16](=[O:18])[CH2:15][C:11]1[CH:10]=[CH:9][C:8]2[C:6]3[NH:7][C:2](=[O:1])[C:3]4[N:4]([CH:21]=[CH:22][N:23]=4)[C:5]=3[CH2:14][C:13]=2[CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)NCc1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 0.618 g of ethyl [4,5-dihydro-4-oxo-10H -imidazo[1,2-a]indeno[1-,2-e]pyrazin-8-yl]acetate and 10 ml of benzylamine is heated at 140° C. for 17 hours under a nitrogen atmosphere. After returning to room temperature, 50 ml of dichloromethane are added to the reaction mixture. The solid formed is filtered, washed with dichloromethane and then recrystallized from 25 ml of dimethylformamide. After drying under reduced pressure (1 mbar) at 60° C., 0.65 g of N-benzyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)acetamide is thus obtained, which product has a melting point greater than 260° C. (Analysis; % Calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64; % Calculated C: 71.1, H: 5.0, N: 15.2, O: 9.1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([O:28]CC)=[O:27])=[CH:9]2.Cl>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=[O:27])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)O)cc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
Ethyl 5-(2-methoxyethoxy)-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylate (2.8 g) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and ethanol (12 mL), 1N aqueous sodium hydroxide solution (12 mL) was added, and the mixture was stirred at 60° C. for 1.5 hr. The reaction solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate-hexane to give the title compound (2.5 g, yield 95%) as a white solid. melting point 174-175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]=[N:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:21])[C:19]#[CH:20].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[CH:20]=[C:19]([CH2:18][OH:21])[O:15][N:14]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: ON=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved in a solvent mixture of ethanol and water (3:1, 100 ml) in the concentration of 0.2 M while stirring. NH2OH—HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol) were added thereto, which was then stirred for about 30 min at room temperature. The completion of reaction was confirmed by liquid chromatography, and water and ethanol were distilled off under reduced pressure to give a pale yellow solid compound. This solid compound was extracted three times with water and ethyl acetate, and the organic solvent layer was subjected to the condition of reduced pressure. The crude compound was recrystallized from hexane/ethyl acetate (10:1) to give a compound as a white solid. Thus obtained solid 4-benzyloxy-benzaldehydeoxime (2.27 g, 10 mmol; a compound of 92% purity) was dissolved in methylene chloride (40 ml, 0.25 M), and propargyl alcohol (1.77 ml, 30 mmol) was added thereto. To this solution was very slowly added in drops 10% NaOCl (13.7 ml, 20 mmol) at 0° C. by using a dropping funnel. After all NaOCl was added, the mixture was stirred for about 5 h during which the temperature was slowly raised to room temperature. After the completion of reaction was confirmed by liquid chromatography, the reaction mixture was distilled under reduced pressure to evaporate methylene chloride. Water (200 ml) was added to the residue, and the resulting solid was filtered. The compound thus filtered was washed with excess water and then finally washed with diethyl ether. The solid compound thus obtained was recrystallized from ethyl acetate/hexane (1:2) to give [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white solid (Yield: 2.5 g). Chlorosulfonyl isocyanate (1.04 ml, 12 mmol) was slowly added to the THF solution (50 ml, 0.2 M) containing [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in a 250 ml flask at −78° C. After disappearance of all the starting materials was confirmed by liquid chromatography, water was added to the reaction solution. After 1 h, distillation under reduced pressure was carried out to evaporate THF. Water (100 ml) was added thereto, and the resulting solid was filtered. Thus filtered solid was washed with 100 me of water and ethyl acetate/hexane (1:2) solution, and dried to give 3.4 g of the crude product (Purity: 95.9%). This crude product was recrystallized from ethyl acetate/hexane/methylene chloride (1:4:1) solution containing 1% methanol to give 2.743 g of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (CBI) in the purity of 99%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:8][Br:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
A 500 mL round-bottomed flask equipped with a magnetic stirrer was charged with 3.6 g of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl alcohol and 25 mL of anhydrous CH2Cl2. The solution was cooled in an ice water bath and was treated with 5.68 g of dibromotriphenylphosphorane (Aldrich). The reaction mixture was warmed to RT, stirred for 2.5 h and then diluted with 100 mL of CH2Cl2. The resulting solution was washed with 5% aqueous NaHCO3 (4×60 mL), dried over anhydrous MgSO4 and concentrated to give a white solid. The crude product was purified by flash chromatography on silica gel (95:5 hexane:EtOAc) to afford 3.86 g (88%) of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl bromide as a white crystalline solid, m.p. 54-55° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8].[CH:22](=O)[CH3:23].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:22]([CH3:23])=[N:8][C:7]=2[CH:9]=1
Reactant: COCCNc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To a solution of 2-(2-(2-methoxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 51-1) (98 mg, 0.346 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 65.1 μL, 1.66 mmol) and oxone (213 mg, 0.346 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (41.4 mg, 39% yield) as light brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:31][N:30]=[N:29][N:26]=3)=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:27][CH:28]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(-c2nnn[nH]2)cc1
Reaction time: 48 h
Yield: 45.5 %

Procedure:
A suspension of methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (220 mg, 0.55 mmol), sodium azide (43 mg, 0.66 mmol), and triethylamine hydrochloride (91 mg, 0.66 mmol) in anhydrous ethylene glycol dimethyl ether (3 mL) was fluxed for 48 h. Reaction mixture was concentrated, resuspended in water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with 0.5 N HCl solution and brine, dried over MgSO4. After filtration, the filtrate was concentrated to give methyl 3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)-amino]-propionate (112 mg, 0.25 mmol).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C:29](=[O:30])[CH2:28][C@H:27]6[CH2:31][NH:32][CH2:33][C@H:26]6[CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39]=O.[Na]>C1COCC1>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C:29](=[O:30])[CH2:28][C@H:27]6[CH2:31][N:32]([CH3:39])[CH2:33][C@H:26]6[CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CNC[C@@H]5CC4=O)cn3)nc2n1C1CCCCCC1
Agent: [Na]
Solvent: C1CCOC1
Product: CN1C[C@@H]2CC(=O)N(c3ccc(Nc4ncc5cc(C(=O)N(C)C)n(C6CCCCCC6)c5n4)nc3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
To a solution of 7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (from example 89, enantiomer-2) (66 mg, 0.128 mmol, 1 eq) in THF (2.0 mL) was added 37% aquous solution of formaldehyde (0.048 mL, 0.639 mmol, 5 eq). The reaction mixture was stirred at room temperature for 5 minutes. Solid sodium triacetoxyhydroborate (81 mg, 0.383 mmol, 3 eq was added into the mixture. The reaction was stirred for 10 more minutes and quenched with a drop of TEA and naturalized with amonia in methanol. The residue was concentrated under vacuum and purified by column chromatography (NH3/MeOH/CH2Cl2) to provide 7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7a R)-2-methyl-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (67 mg) in quantitative yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.63 (d, J=9.09 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J=2.53 Hz, 1H), 7.67 (dd, J1=9.09, J2=2.53 Hz, 1H), 6.44 (s, 1H), 4.73 (s, 3H), 4.52 (m, 1H), 3.83 (dd, J1=13.14, J2=4.04 Hz, 1H), 3.65 (dd, J1=13.14, J2=4.04 Hz, 1H), 3.17 (s, 6H), 2.91-2.51 (m, 7H), 2.36 (m, 4H), 2.01 (m, 2H), 1.87 (m, 2H), 1.79-1.51 (m, 5H); HRMS m/z 531.3219 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:46])[CH2:3][NH:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]([NH:9][C@H:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][CH:20]=2)[C:14]2[CH:40]=[CH:41][CH:42]=[CH:43][C:13]=2[S:12][CH2:11]1)=[O:8].[C:47]([O:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C:52]([NH:54][CH2:55][C:56]([O:1][C@H:2]([CH3:46])[CH2:3][NH:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]([NH:9][C@H:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])=[CH:21][CH:20]=2)[C:14]2[CH:40]=[CH:41][CH:42]=[CH:43][C:13]=2[S:12][CH2:11]1)=[O:8])=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OC(=O)CNC(=O)OC(C)(C)C

Procedure:
This intermediate is prepared from the intermediate obtained in Step B and N-t-butoxycarbonyl glycine according to the procedure described in Example 9, Step C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][N:5]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:9]2=[O:24])[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)OC(C)(C)C)C2=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 41.6 %

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (600 mg, 1.693 mmol) (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) in acetone (20 ml), 2-chloro-N,N-dimethylethanamine hydrochloride (366 mg, 2.54 mmol), potassium carbonate (468 mg, 3.39 mmol) and potassium iodide (281 mg, 1.693 mmol) were added. The resulting mixture was stirred at 50° C. for 48 hours. The insoluble inorganic salts were filtered off, and the filtrate was evaporated. The crude was purified by was crystallization from EtOH affording tert-butyl 2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (300 mg, 0.705 mmol, 41.6% yield, MS/ESI+ 426.0 [MH]+).