Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH2:50])=[O:49])=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:44]3[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH2:50])=[CH:46][CH:45]=3)=[O:16])[CH:12]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=O)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To the solution of 1 (naproxen, 4 g, 17.4 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (2.59 g, 19.14 mmol) and DCC (2.59 g, 19.14 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 3.58 g, 26.1 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)-propanoate (5) was obtained (1.91 g, 32% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70]Br)[CH:65]=1>C(#N)C>[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]3[N:10]([C:32](=[O:33])[C:34]4[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=4[F:40])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:14]=2[O:30][CH3:31])[CH:65]=1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: COC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OC)c1
Reaction time: 0.5 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (0.02 mmol) is treated with tetrabutylammonium fluoride (1 M in THF) (0.04 mmol) at room temperature for 30 minutes. 3-Bromomethyl-benzoic acid methyl ester (0.04 mmol) is then added. After 30 minutes, the reaction is complete as determined by LC/MS. The mixture is diluted with acetonitrile and purified by preparative LC/MS (20-100% MeCN/H2O) to give 3-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoic acid methyl ester as white solid after evaporation of solvent: 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.47-7.55 (m, 4H), 7.01-7.07 (m, 3H), 6.94 (t, J=8.3 Hz, 2H), 6.77 (t, J=8.5 Hz, 2H), 5.16 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H). LC/MS (ES+: (M+1) 610.9.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:6]2[CH2:5][CH2:4][N:3]([CH:8]3[CH2:17][CH2:16][C:15]4[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=4[CH2:9]3)[C:2](=[O:1])[CH2:7]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (20 mg, 0.078 mmol) in DMF (1 mL) was added 1-(2-Iodoethyl)-4-nitrobenzene (26 mg, 0.094 mmol) and K2CO3 (43 mg, 0.31 mmol). The mixture was allowed to stir at RT for 16 hours. LC showed product formation. The desired product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 405 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1.[C-]#N.[Na+].[I-].[Na+].[CH3:19][N:20](C=O)C>O>[C:19]([CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1)#[N:20]
Reactant: CN(C)C=O
Reactant: ClCCC1OCCc2ccccc21
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: N#CCCC1OCCc2ccccc21

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.9874 g, 5.02 mmol), sodium cyanide (0.3793 g, 7.74 mmol), sodium iodide (a few mg) and DMF (5 ml) is heated overnight at 856. Additional sodium cyanide (0.5826 g, 11.9 mmol) is then added in two portions, along with DMF (14 ml) and a few mgs of sodium iodide. The mixture is heated at 97° for another two days and then cooled and poured into water. The mixture is extracted several times with ethyl acetate and the combined organic phase is backwashed twice with water, followed by two saline washes, then dried over magnesium sulfate and concentrated to dryness. The crude product is chromatographed on silica gel eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give 1-(2-cyanoethyl)isochroman (LXVI), NMR (CDCl3) 2.11, 2.27-2.72, 2.98, 3.77, 4.13, 4.86 and 7.17 δ.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>>[O:1]1[CH2:4][CH:3]([O:5][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:2]1
Reactant: OC1COC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1OC1COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of oxetan-3-ol (1.0 g, 13.50 mmol) were added triphenylphosphine (4.25 g, 16.20 mmol) and 2-hydroxyisoindoline-1,3-dione (2.42 g, 14.85 mmol). After stirring at rt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (3.28 g, 16.20 mmol) was added. After stirring at 30° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified with column chromatography on silica gel (gradient hexanes:EtOAc) to give a colorless oil 2-(oxetan-3-yloxy)isoindoline-1,3-dione (400 mg, 6%). LCMS (method B): [MH]+=220, tR=1.67 min.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a 0° C. solution of 1-benzhydryl-3-methylazetidin-3-ol (70 g, 276 mmol) and TEA (53.1 g, 525 mmol) in DCM (700 mL) was added drop-wise methanesulfonyl chloride (57 g, 497 mmol). The reaction mixture was stirred for 2 h then filtered and the filter cake was washed with DCM (3×50 mL). The filtrate was washed with water (3×100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (90 g, 98%) as a brown solid, which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.33 (m, 4H), 7.26 (m, 2H), 4.55 (brs, 1H), 3.46 (m, 4H), 3.07 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].O>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]=[CH:15][C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: O=c1[nH]c2ccc(C(O)CCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=CCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of 6.7 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-hydroxypropyl}-3H-benzoxazol-2-one [obtainable by hydrogenation of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-oxopropyl}-3H-benzoxazol-2-one, which can be obtained by reacting 4-(4-fluorobenzyl)piperidine and 6-(3-chloropropionyl)-3H-benzoxazol-2-one] in 70 ml of dioxane is heated under reflux with 7 ml of concentrated HCl for 1.5 h. The mixture is cooled and 8.5 g of NaHCO3 and 70 ml of water are added. 30 ml of dichloromethane are added and the mixture is stirred for 30 minutes. The precipitate is separated off, washed with acetone and ether and dried to give 5.7 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one (“A”), m.p. 202-203.5°; hydrochloride: m.p. 220-223°.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[N:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([O:18][CH2:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)[N:8]=1)=[O:6].CO>O1CCCC1>[CH:20]1([CH2:19][O:18][C:9]2[N:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=[N:11][C:10]=2[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Sodium hydroxide 2M (10 mL) was added to a solution of the 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester (2.2 g, 7.4 mmol) in a (1:1) mixture of methanol and tetrahydrofuran (30 mL), the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ether (30 mL) and extracted with water (50 mL), the aqueous layer was washed with ether (2×50 mL) until only product remained in the aqueous layer. The aqueous layer was cooled to 0° C. and acidified with concentrated hydrochloric acid until precipitation was observed. The precipitate was filtered and dried in vacuo to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid as a cream solid 1.65 g (80% yield) LC@215 nm; Rt 1.98: 93%, m/z (ES+): 278 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[C:23](O)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[C:23](=[O:25])[CH3:24]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Reactant: CC(=O)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(C)=O

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 56 using 4-(4-methoxyphenoxy)-5-methyl-7-nitroindane instead of ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate and using acetic acid instead of 4-fluorophenylacetic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:22]1([C:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@H]1CCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3 H); 3.52-3.41 (m, 3 H); 3.25-3.11 (m, 2 H); 3.10-2.97 (m, 2 H); 2.89 (dt, J=11.4, 7.5 Hz, 1 H); 2.11-1.99 (m, 1 H); 2.01-1.91 (m, 2 H) and 1.93-1.82 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3]1.CCN(CC)CC.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34].O>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[CH2:13][CH2:12][N:11]([C:4]3[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)=[C:27]([C:33]([F:34])([F:35])[F:36])[CH:28]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(N2CCN(Cc3ccc(F)cc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The compound 54 is prepared according to the synthesis method 2: 0.26 g (1.17 mmol) of derivative 12a is placed in 3 mL of toluene in the presence of 0.24 mL (1.75 mmol) of NEt3 and of 0.3 g (1.17 mmol) of 1-bromomethyl-4-fluoro-2-trifluoromethyl-benzene. This mixture is stirred 2 h at 110° C. The medium is taken up with water and extracted with AcOEt. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2-AcOEt: 95-5). 0.37 g of a yellow oil are isolated (yield: 79%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[C:18]2=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[C:17]2[CH:16]=[N:15]1.[I:36]I>C1COCC1.O>[I:36][C:24]1[N:23]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])[C:20]2=[N:21][CH:22]=[C:17]3[CH:16]=[N:15][N:14]([CH3:13])[C:18]3=[C:19]2[CH:25]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnn(C)c23)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
Diisopropylamine (0.20 mL, 1.5 mmol) in THF (1.5 mL) was cooled to about −74° C. A solution of n-BuLi (1.6 M solution in cyclohexane, 1.03 mL, 1.65 mmol) was added drop-wise over about 15 min. After about 20 min, the solution was added to 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.250 g, 0.766 mmol) in THF (10 mL) at about −74° C. over about 10 min. After about 1 h at about −74° C., a solution of iodine (0.226 g, 0.889 mmol) in THF (5 mL) was added over about 5 min. After about 2 h at about −74° C., water (20 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-40% EtOAc in heptane to give 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.27 g, 78%): LC/MS (Table 2, Method d) Rt=2.34 min; MS m/z: 453 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].C[O-].[Na+].[Cl-:18].[NH4+:19]>CO>[ClH:18].[NH2:2][C:1](=[NH:19])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCNC(=O)OCc1ccccc1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of benzyl cyanomethylcarbamate (65.4 g, 344 mmol) in methanol was added sodium methoxide (7.86 mL, 34.4 mmol, 25% in methanol). The mixture was stirred at ambient temperature for 24 h. Ammonium chloride (18.4 g, 344 mmol) was then added. The mixture was stirred at ambient temperature for another 24 h, and concentrated under reduced pressure. The resulting material was added into hexane/ethyl acetate (1:1) (240 mL) and ether (50 mL), stirred at ambient temperature for 1.5 h, then filtered to provide the title compound as a pale colored solid (78.8 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (br. s., 4H), 7.78 (t, J=5.5 Hz, 1H), 7.24-7.47 (m, 5H), 5.07 (s, 2H), 3.98 (d, J=5.5 Hz, 2H). MS m/z 208.2 (M+1), retention time=0.64 min.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH3:26]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (1.04 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1→0/1) to give the title compound as a colorless solid (yield: 528.3 mg, 73%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:43][C:44]1[C:45]([OH:54])=[C:46]([CH:51]=[CH:52][CH:53]=1)[C:47]([O:49][CH3:50])=[O:48].Cl>CN(C=O)C.O>[OH:54][C:45]1[C:44]([NH:43][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:53][CH:52]=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)c2cc3ccccc3[nH]2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 170.8 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid (965 mg, 1.2 mmol) in DMF (15 mL) was added HOBt (740 mg, 1.1 mmol), DIPEA (1.98 g, 3.0 mmol) and EDCI (1.05 g, 1.1 mmol). The mixture was stirred at room temperature for 30 min. Then methyl 3-amino-2-hydroxybenzoate (835 mg, 1 mmol) was added. The mixture was stirred at room temperature for 10 hr. To the resulting mixture, water (10 mL) and aqueous hydrochloric acid (1 N) were added to pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, dried by anhydrous sodium sulfate and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1) to obtain methyl 2-hydroxy-3-(1H-indole-2-carboxamido)benzoate as a solid (530 mg, yield 26%). LC-MS (ESI) m/z 296 [M+1]−.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:14]2[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([F:9])[CH:15]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
N-Ethylpiperazine (4.8 mL, 37.7 mmol, 1.2 equiv) is added to a mixture of 2,4-difluoronitrobenzene (5 g, 31.4 mmol) and potassium carbonate (8.7 g, 62.9 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow oil: ES-MS: 254.1 [MH]+; TLC: Rf=0.67 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:29][CH:19]3[CH2:20][N:21]([C:23](=O)[C:24]([F:27])([F:26])[F:25])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.CSC.B>C1COCC1>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:17][CH:18]3[CH2:22][N:21]([CH2:23][C:24]([F:26])([F:25])[F:27])[CH2:20][CH:19]3[CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)C(F)(F)F)CC4C3)n2)cn1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(CC(F)(F)F)CC4C3)n2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a solution of 1-[5-[[5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]amino]-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-2,2,2-trifluoro-ethanone (0.89 g, 2.10 mmol) in THF (20 mL) was added a solution of borane dimethyl sulfide complex (1 mmol/L in THF, 6 mL, 6 mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C. for 10 min and then heated to reflux overnight. The reaction was quenched with 6 M HCl aqueous solution (2 mL) then stirred at rt for 1 h and concentrated in vacuo. The residue was adjusted to pH=10 with a 50% NaOH solution, then diluted with water (50 mL), and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (0.16 g, 19%).