Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:6])=O.C1(NO)C=CC=CC=1.CC[O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1.C(O)C>[O:23]=[C:24]1[O:6][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: NN
Agent: ONc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)oc1=O
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
Hydrazine hydrate (1.7 g) was added dropwise over 30 min to a stirred suspension of 5% Rh—C (wet, 110 mg) and nitrobenzene (4.1 g) in THF (20 mL) at 15° C. controlled by ice-bath. The reaction mixture was warmed to 25-30° C. for 2 h, followed by filtration. The filtrate was diluted with an equal volume of dichloromethane, dried over sodium sulfate, then condensed to a small volume. Addition of petroleum ether to this solution led to the formation of a needle-like white solid as the fairly pure product of phenyl hydroxyamine (3.2 g, 86%). The reaction mixture of phenyl hydroxyamine (2.675 g, 25 mmol), diethyl ethoxymethylene malonate (4.324 g, 20 mmol) and ethanol (20 mL) was stirred at RT for 12 h to form a large amount of solid, which after warming on a water-bath for 3 h disappeared and reappeared when the reaction mixture was cooled down to RT. Filtration and washing with ethanol provided the title compound as white crystal like solid (4.25 g, 91%). 1H NMR (200 MHz, CDCl3) δ (ppm): 8.40 (s, 1H), 7.46-7.28 (m, 5H), 4.23(q, J=7.1 Hz, 2H). 1.31 (t, J.=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C@H:39]2[CH2:44][NH:43][CH2:42][CH2:41][NH:40]2)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C@@H:39]2[NH:40][CH2:41][CH2:42][N:43]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:44]2)=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Agent: COS(=O)(=O)C(F)(F)F
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)cc1
Yield: 71.2 %

Procedure:
Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.40 g, 1.8 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.625 g): mass spectrum (APCI+, m/e): 488 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.58 (s, 1H), 7.13–7.03 (m, 2H), 6.99–6.86 (m, 3H), 6.85–6.78 (m, 2H), 6.75–6.69 (m, 1H), 4.22–3.97 (br. m, 2H), 3.70 (s, 3H), 3.44–2.87 (m, 6H), 2.68–2.46 (m, 2H), 1.84–1.71 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH:24]=2)[N:10]=1.O[Li].O>C1COCC1.O.C(Cl)Cl>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([N:23]2[CH:24]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=4[CH2:4][C:3]([OH:42])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)[CH:21]=[N:22]2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A135) (300 mg, 0.510 mmol) and LiOH.H2O (855 mg, 20.4 mmol) in THF (20 mL) and H2O (1 mL) was stirred at 40° C. overnight. The mixture was diluted with DCM (50 mL) and water (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined washings were dried (Na2SO4) and the volatiles were removed in vacuo to yield the title compound (A136) as a yellow oil (270 mg, 92%). LCMS-A: rt 6.679 min; m/z 575.2 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:9][O-].[Na+].CI>CO>[CH3:9][S:3][C:2]1[NH:1][CH:8]=[CH:7][C:5](=[O:6])[N:4]=1
Reactant: C[O-]
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(=O)cc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20 g (153 mmol) 2-thiouracil are suspended in 250 mL MeOH and then 8.7 g (152.9 mmol, 1 eq) sodium methoxide are added. The solution is stirred for 5 min at RT and then 12.4 mL (198.8 mmol, 1.3 eq) methyl iodide are added dropwise. The reaction mixture is stirred overnight, then poured onto water and extracted 3× with approx. 150 mL chloroform. The combined organic phases are dried on MgSO4, the solvent is eliminated in vacuo and 16 g E-1 are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]=1[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30]>C(Cl)Cl.CC(=O)OCC>[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:16][NH:15][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([CH3:19])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH2:20][CH3:21])[CH:11]=2)=[O:38])=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: Cc1cc(C(=O)Cl)ccc1OC(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(=O)NNC(=O)c2ccc(OC(C)C)c(C)c2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
To a suspension of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (1.12 g, 3.95 mmol) in DCM (20 mL), triethylamine (500 mg, 4.94 mmol) is added. The clear solution is cooled to 5° C. before a solution of 4-isopropoxy-3-methyl-benzoic acid chloride (700 mg, 3.29 mmol) in DCM (10 mL) is added dropwise. The suspension is stirred at rt for 1 h before it is diluted with EA, washed with 1 N aq. HCl, followed by water, dried over MgSO4, filtered, concentrated and dried to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(4-isopropoxy-3-methyl-benzoyl)-hydrazide (1.57 g) as a white solid; LC-MS: tR=1.05 min, [M+1]+=461.66.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[O:16])=[CH:5][CH:4]=1.[CH2:17]([C:20]1[NH:21][C:22]2[C:28]([CH3:29])=[CH:27][C:26]([C:30]3[N:34]([CH3:35])C4C=CC=CC=4N=3)=[CH:25][C:23]=2[N:24]=1)[CH2:18][CH3:19].[OH-].[Na+].O.[CH3:43][N:44](C)[C:45](=O)C>>[CH2:17]([C:20]1[N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([CH:15]=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[C:23]2[CH:25]=[C:26]([C:30]3[N:34]=[CH:35][N:44]([CH3:45])[CH:43]=3)[CH:27]=[C:28]([CH3:29])[C:22]=2[N:21]=1)[CH2:18][CH3:19]
Reactant: CC(=O)N(C)C
Reactant: O=Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2cc(-c3nc4ccccc4n3C)cc(C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 4-bromomethyl-2′-formylbiphenyl (I) (1.0 g, 3.6 mmol), 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2-yl)benzimidazole (1.1 g, 3.6 mmol) and NaOH (0.15 g, 3.6 mmol) in 25 ml of N,N-dimethylacetamide is stirred at room temperature under argon atmosphere for 20 hours. Reaction mixture into poured into 160 ml of water and extracted 4 times with 40 ml of ethyl acetate. Combined organic extracts are dried over MgSO4 and evaporated under reduced pressure. Crude amorphous product is obtained in yield: 3.01 g.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:37])[CH:28](Br)[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:28]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([OH:26])=[O:37])[C:3](=[O:15])[CH:2]=1
Reactant: COC(=O)C(Br)CC1CCOCC1
Reactant: Oc1c(F)cccc1F
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (Intermediate 14) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid as a white solid (223 mg, 88% for the final step); ES+-HRMS m/e calcd for C18H18N2O5F2 [M+H+] 381.1257, found 381.1257. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.37 (m, 3H), 1.38-1.49 (m, 1H), 1.53-1.68 (m, 1H), 1.86-2.03 (m, 1H), 2.04-2.17 (m, 1H), 3.04-3.29 (m, 2H), 3.70-3.88 (m, 2H), 5.42 (dd, J=10.7, 4.3 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 7.33-7.43 (m, 2H), 7.43-7.56 (m, 1H), 8.28 (d, J=2.8 Hz, 1H), 13.13 (br s, 1H).
Reaction SMILES: ClC1C=CC=CC=1C.[S:9]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([F:24])[F:23])=O)=[CH:12][C:11]2[CH:26]=[CH:27][CH:28]=[CH:29][C:10]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OC(C)C)(C)C>CCCCCC>[S:9]1[C:13]([C:14](=[S:39])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([F:24])[F:23])=[CH:12][C:11]2[CH:26]=[CH:27][CH:28]=[CH:29][C:10]1=2
Reactant: CC(CCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1Cl
Solvent: CCCCCC
Product: CC(CCCCOC(=S)c1cc2ccccc2s1)=C(F)F
Yield: 81.4 %

Procedure:
To 5 ml of 2-chlorotoluene was dissolved 0.20 g (0.64 mmol) of 6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate, followed by the addition of 0.26 g (0.64 mmol) of Lawesson's reagent and stirring by heating under refluxing for 4 hours. To the reaction liquid were added 2 ml of isopropyl ether and 10 ml of hexane and precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:30) to obtain 0.17 g (yield: 81%) of O-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)N=CC=3)N(CC2)C1.[OH-:23].[K+].[CH:25]([OH:28])(C)C>>[CH3:25][O:28][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1=[O:23]
Reactant: CC(C)O
Reactant: [OH-]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: [K+]
Product: COC1CCCCC1=O

Procedure:
Example 1 is repeated, except that isopropanol is used as solvent, 10 mg of hydrocinchonidine are used as modifier and 100 mg of catalyst are used. In addition, 7 mg of KOH are added. The yield is 0.75 g of product of 90% purity containing 10% solvent (88%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CC1CC1C(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of HATU (101 mg), 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), N,N-diisopropylethylamine (0.130 ml), 2-methylcyclopropanecarboxylic acid (0.049 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (3 mg) as a diastereomeric mixture. The filtrate was concentrated in vacuo and the precipitate was recrystallized from THF to give the title compound (17 mg) as a diastereomeric mixture.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[C:12](O)(=[O:14])[CH3:13]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:11][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1
Reactant: CC(=O)O
Reactant: Oc1ccc2c(c1)CCCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)CCCC2
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To 5,6,7,8-tetrahydro-2-naphthol 14 (10 mmol, 1.48 g) placed in a flask flushed with argon at room temperature, was slowly added TiCl4 (11 mmol, 1.2 mL). The resulting dark cherry-colored mixture was stirred at room temperature, and when gas evolution ceased, 15 mmol (1.07 mL) of acetic acid was added to the solid. The resulting thick solution was stirred at room temperature for 15 min, then brought to 120° C. and left to stir at this temperature for an additional hour. The reaction mixture was then cooled to room temperature, diluted with CH2Cl2 (30 mL) and quenched with H2O (30 mL). A cloudy solution was obtained which was easily extracted with CH2Cl2. The organic layer was washed with H2O (2×30 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a mixture of hexanes/EtOAc (95/5) to give 15 as a yellowish solid (1.14 g, 59% yield). mp 70-72° C.; 1H NMR (CDCl3) δ 1.77 (m, 4H), 2.59 (s, 3H), 2.76 (m, 4H), 6.68 (s, 1H), 7.41 (s, 1H), 11.96 (s, 1H); 13C NMR (CDCl3) δ 22.87, 23.42, 26,72, 28.82, 30.17, 117.82, 118.21, 128.10, 131.04, 147.71, 160.09, 204.16; IR (KBr, ν cm−1) 2934, 1621, 1491, 1344; MS (ESI) 191 (M+1). Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.91; H, 7.46.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]3[C:39]4=[C:40]5[C:31]([CH:32]=[CH:33][CH:34]=[C:35]5[CH:36]=[CH:37][C:38]=24)=[CH:30][CH:29]=3)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:41](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:50]1[CH:57]=[CH:56][C:53]([O:54][CH3:55])=[CH:52][CH:51]=1)[C:42]1[CH:49]=[CH:48][C:45]([O:46][CH3:47])=[CH:44][CH:43]=1>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[C:38]3[C:39]4=[C:40]5[C:35](=[CH:36][CH:37]=3)[CH:34]=[CH:33][CH:32]=[C:31]5[CH:30]=[CH:29][C:28]4=[CH:27][CH:26]=2)[CH:13]=[C:14]([CH2:16][O:17][C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:57]=[CH:56][C:53]([O:54][CH3:55])=[CH:52][CH:51]=2)[C:42]2[CH:49]=[CH:48][C:45]([O:46][CH3:47])=[CH:44][CH:43]=2)[CH:15]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Solvent: CO
Product: COc1ccc(C(OCc2cc(CO)cc(-c3ccc4ccc5cccc6ccc3c4c56)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 27 h

Procedure:
14.5 ml of pyrizine were added to dissolve 0.932 g of Compound (14) in an Ar atmosphere, and 1.27 g (3.77 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 27 hours in an Ar atmosphere. After extraction with chloroform, the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4632 g (0.72 mmol, 3-step 30%) of Compound (14) was isolated by silica gel chromatography (chloroform only→chloroform:methanol=100:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.137 g, 0.5 mmol) was mixed with 3,5-dichlorophenyl isothiocyanate (0.111 g, 0.54 mmol) in ethyl acetate (10 mL) and heated briefly to 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was concentrated to dryness and triturated with hexanes/ethyl acetate, and the insoluble solid collected by filtration (0.214 g), mp 203-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]([NH:31][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=2)[CH2:24][NH:23][C:22](=[O:32])[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)COCc1ccc(Br)cc1
Reactant: Nc1cccc(CNC(=O)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccc(Br)cc1)Nc1cccc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 67A (245 mg, 1 mmol) and 66A (268 mg, 1.05 mmol) in DMF (4 mL), was added EDCI (288 mg, 1.5 mmol), HOAt (14 mg, 0.1 mmol) and DIEA (0.54 mL, 3 mmol). The mixture was stirred rt for 16 h, then was quenched with water and extracted with EtOAc (3×20 mL). The organic layer washed by brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-40% EtOAc in hexanes) gave 67B (300 mg, 62%). MS (ESI) m/z 483.3 (M+H)+.
Reaction SMILES: [OH-:1].[NH4+:2].[C:3](=[O:5])=[O:4]>>[C:3](=[O:1])([O-:5])[O-:4].[NH4+:2].[NH4+:2].[C:3](=[O:1])([OH:5])[O-:4]
Reactant: O=C=O
Reactant: [OH-]
Agent: [NH4+]
Product: O=C([O-])O
Product: O=C([O-])[O-]

Procedure:
Step 3, Second Recycling of Filtrate: It was speculated that excess of ammonium hydroxide together with carbon dioxide resulted with ammonium carbonate or bicarbonate, and that the limiting factor in precipitation was the quantity calcium ions. An aliquot of 100 mL of the filtrate (total volume 3370 mL) was mixed with 400 mL CaSO4.2H2O solution (2.0 g/L). A precipitate formed. It was filtered and oven dried. 0.274 grams were isolated. Additional CaSO4.2H2O solution did not cause further precipitation from this aliquot of the filtrate. Based on this measurement it is calculated that a total of 9.23 g of calcium carbonate could be precipitated from the filtrate. The product isolated was identified by XRD as being calcite.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH3:41])[O:37][CH2:36][CH:35]([CH2:38]CO)[CH2:34][O:33]1>>[Na:1].[CH3:31][C:32]1([CH3:41])[O:37][CH2:36][CH:35]([CH2:38][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:34][O:33]1
Reactant: CC1(C)OCC(CCO)CO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 2 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethanol obtained in the step (28a) to obtain the title compound (58 mg, total yield: 2.0%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([C@H:36]([OH:38])[CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:38][C@H:36]([CH3:37])[C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:23])[CH2:34][OH:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](O)[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (2R,3R)-2-aminobutane-1,3-diol (25 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by trituration with 1:1 heptane/dichloromethane to afford 115 mg (96%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a white solid. MS: [M+H]+=529.