Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][CH2:67][C:66]([CH2:78][OH:79])([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=2[F:77])[CH2:65]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:77][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][C:66]1([CH2:78][OH:79])[CH2:67][CH2:68][CH2:69][N:64]([NH:63][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:65]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NN1CCCC(CO)(Cc2ccccc2F)C1
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: CN(C)C=O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Cc5ccccc5F)C4)cc23)ccn1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (605 mg, 1.22 mmol), HATU (572 mg, 1.50 mmol) and (1-amino-3-(2-fluorobenzyl)piperidin-3-yl)methanol (258 mg, 0.94 mmol) was dissolved in dimethylformamide (3 mL). Diisopropylethylamine (0.819 mL, 4.7 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[O:4].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:40][C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=1)=[O:4]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CNC(C(=O)OC)C4)cc3)nc2n(CCC)c1=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Solvent: O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)OC)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-pyrrolidine-2-carboxylic acid methyl ester (50 mg, 0.106 mmol) and TEA (32 mg, 0.319 mmol) in DCM (5 ml), 3-trifluoro methyl benzyl bromide (30 mg, 0.127 mmol) was added at 0° C. Reaction mixture was stirred at room temperature for 4 hr. Water was added into it and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid methyl ester as an off white solid (25 mg, 37%).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Li+].[Li+].[CH2:24]([O:31][C:32](=[O:35])[CH2:33]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:31][C:32](=[O:35])[CH2:33][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cc1cc(Cl)ccc1O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,2′-Methylene-bis(4-chloro-phenol) (12 g, 44.6 mmol) is dissolved in DMF (100 mL). Lithium carbonate (3.3 g, 44.6 mmol) is added, followed by benzyl-2-bromoacetate (7.7 mL, 49 mmol). The suspension is stirred at 80° C. for 8 hours. Further benzyl-2-bromoacetate (1 mL, 6.4 mmol) is added and stirring continued at 100° C. for 4 hours. The reaction mixture is evaporated to dryness, water is added to the residue which is acidified to pH 1 with 2 M aqueous HCl and extracted with EtOAc. The organic layer is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash column chromatography over silica gel eluting with 4:1 iso-hexane:EtOAc. The product is suspended in iso-hexane, dissolved in the minimum volume of EtOAc, seeded and left to stand. The resultant solid is collected by filtration, washed with iso-hexane and dried to give [4-chloro-2-(5-chloro-2-hydroxy-benzyl)-phenoxy]-acetic acid benzyl ester; m.p.=135-137° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1.O.[SH2:20].[Na].Cl>O>[SH:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(Cl)nc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 1 h

Procedure:
A mixture of 2.30 g of methyl 5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 2.0 g of sodium hydrogen sulphide monohydrate in 60 ml of water was stirred at 60° for 1 hour. The reaction mixture was cooled, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a vacuum until crystallization occurred. Petroleum ether was added and the solid product was filtered off under suction. There was obtained methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]1([C:18]2[S:19][CH:20]=[C:21]([C:23]([N:25]3[CH2:30][C:29]4([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[O:28][CH2:27][CH2:26]3)=[O:24])[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][C:29]2([O:28][CH2:27][CH2:26][N:25]([C:23]([C:21]3[N:22]=[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[S:19][CH:20]=3)=[O:24])[CH2:30]2)[CH2:31][CH2:32]1
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Reactant: OCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-bromo-1-nonanol (0.346 g) in MeCN (3 mL) was added to solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.355 g) and triethylamine (0.288 mL) in MeCN (7 mL). The resulting mixture was stirred at 60° C. under argon for 17 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.378 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11](N)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:23].[Na+].C([O-])(O)=O.[Na+]>Cl.O>[NH2:21][C:10]1[C:11]([OH:23])=[N:12][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: O=N[O-]
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)nc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a cooled solution (0° C.) of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 100 mg, 0.36 mmol) in HCl 1N (1 mL) was added dropwise a solution of sodium nitrite (35 mg, 0.50 mmol) in water (0.6 mL). The reaction was stirred for 1 h at room temperature and after this period was driven to pH7 by addition of a NaHCO3 4% solution. The suspension was filtered to leave a solid which was purified by silica gel chromatography eluting with CH2Cl2/MeOH/NH3 (50:8:1) to afford the title compound (37 mg, 36%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.O>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCO
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCOCc1ccc(C(=O)O)cc1

Procedure:
To the suspension of sodium hydride (1.390 g, 95%, 55 mmol) in tetrahydrofuran (150 ml), But-3-en-1-ol (3.966 g, 4.7 ml, 55 mmol) was added. After the reaction mixture was refluxed for 30 min, 4-Bromomethyl-benzoic acid (5.376 g, 25 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C. to generate white precipitate, which was then collected by filtration. The recrystallization of this crude product from hexane/ether yielded pure 4-But-3-enyloxymethyl-benzoic acid as colorless crystal (4.15 g, 80.5%). 1H-NMR (400 MHz, d6-DMSO): 7.91 (d, J=8.2, 2 arom. H); 7.41 (J=8, 2 arom. H); 5.81 (m, —CH═CH2); 5.10 (2 d-like, —CH═CH2); 4.53 (s, —OCH2—C6H4); 3.49 (m, CH2═CH—CH2CH2O); 2.32 (m, CH2═CH—CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 143.72; 135.49; 129.73; 129.28 (2 arom. C); 127.08 (2 arom. C); 116.46; 71.13; 69.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[CH:36][N:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[N:35][CH:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.184 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.093 g, 0.920 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was to stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.053 g (52.42%). 1H NMR (400 MHz, CD3OD): δ 9.21-9.16 (m, 2 H), 8.01-7.94 (m, 2H), 7.81 (br. s., 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.17 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.38 (s, 3H), 1.75 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ −77.43 (TFA), −112.62. LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.ClCCl.[CH3:25][N:26]=[C:27]=[S:28]>O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:27](=[S:28])[NH:26][CH3:25]
Reactant: CN=C=S
Reactant: O=P(O)(O)CCCNO
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Product: CNC(=S)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.3 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), bis(trimethylsilyl)acetamide (10 g) and dichloromethane (30 ml) was stirred at ambient temperature for 3 hours and cooled to 0°-5° C. To the mixture was added methylisothiocyanate (800 mg) under ice-cooling. The reaction mixture was stirred at the same temperature for an hour and concentrated under reduced pressure to give a residue. To this residue was added water (50 ml) and stirred at ambient temperature for 30 minutes. After the remaining dichloromethane was removed by evaporation under reduced pressure, an aditional 50 ml of water was added. The aqueous solution was subjected to a column chromatography using activated charcoal. The column was washed with water (650 ml) and then the object compound was eluted with 70% aqueous acetone. The eluate was concentrated under reduced pressure to give crystals, which were separated by filtration, washed with ethanol and dried to give crystalline 3-[N-hydroxy-N-{(N-methyl)thiocarbamoyl}amino]propylphosphonic acid (320 mg). Further, the ethanol washing was concentrated under reduced pressure to give a residue which was pulvelized to give the same object compound (450 mg). MP 190° C. (dec.).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([O-:7])=[O:6].[N-:15]=[N+:16]=[N-].[Na+]>O.FC(F)(F)C(O)=O>[N:12]([C:11]1[CH:13]=[CH:14][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
A solution of sodium nitrite (761 mg, 11 mmol) in water (5 mL) was added dropwise to a 0° C. solution of 4-nitroaniline (508 mg, 3.68 mmol) in trifluoroacetic acid (5 mL). After stirring for 10 minutes, a solution of sodium azide (1.55 g, 23.9 mmol) was added slowly. The resulting yellow suspension was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-azido-4-nitrobenzene (600 mg, 99%). 1H NMR (400 MHz, CDCl3, δ): 8.16-8.19 (m, 2H), 7.05-7.09 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([C:21]3[N:29]4[C:24]([CH:25]=[CH:26][CH:27]=[CH:28]4)=[C:23]([C:30]4[CH:45]=[CH:44][C:33]([C:34]([O:36]CC5C=CC=CC=5)=[O:35])=[CH:32][CH:31]=4)[C:22]=3[CH3:46])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:47])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CN(C=O)C.C(OC(C)C)(C)C>[C:1]([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([C:21]3[N:29]4[C:24]([CH:25]=[CH:26][CH:27]=[CH:28]4)=[C:23]([C:30]4[CH:45]=[CH:44][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=4)[C:22]=3[CH3:46])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:47])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(-c2ccc(C(=O)OCc3ccccc3)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(C(=O)O)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Palladium on carbon (10% active, 0.2 g) and benzyl 4-(3-{[3-(2-tert-butoxy-2-oxoethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl]carbonyl}-2-methylindolizin-1-yl)benzoate (1 g, 1.55 mmol) are added, under nitrogen, to ammonium formate (0.97 g, 15.54 mmol) in solution in 15 mL of DMF. The reaction mixture is stirred for 3 h at ambient temperature and filtered through Celite, and the filtrate is concentrated to dryness. The solid obtained is taken up in diisopropyl ether. After filtration and drying under vacuum, 732 mg (yield: 85%) of a green solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:27](=[O:29])[CH3:28])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reaction time: 3 h
Yield: 64 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added acetyl chloride (0.02 g, 0.27 mmol) followed by pyridine (0.02 g, 0.21 mmol). After stirring for 3 h, reaction was concentrated and purified by flash chromatography on silica gel with 50% EtOAc/hexane to obtain the product in 64% yield.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:38]=[C:37]2[C:33]([C:34]([Sn](CCCC)(CCCC)CCCC)=[N:35][N:36]2[CH3:39])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:34]3[C:33]4[C:37](=[CH:38][C:30]([S:27]([CH3:26])(=[O:28])=[O:29])=[CH:31][CH:32]=4)[N:36]([CH3:39])[N:35]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(S(C)(=O)=O)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(S(C)(=O)=O)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (110 mg, 0.26 mmol) and 6-methanesulfonyl-1-methyl-3-tributylstannanyl-1H-indazole (crude from Step 3, 330 mg, 0.33 mmol) were dissolved in DMF (1.7 ml). The flask was evacuated and backfilled with argon and tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. for 3 h then allowed to cool to room temperature overnight. The reaction was quenched with water and extracted with diethyl ether (2×) and EtOAc. The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc) to afford 79 mg (55%) of 2-(6-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 8.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (574.6 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (907.5 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (113 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[O:12][CH2:13][C:14](=[O:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a solution of ethyl 2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, 0.90 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.90 mmol) in ethanol (6.0 mL), piperidine (0.045 mL, 0.45 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.13 g, y. 35%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:10]=1>>[CH:1]1([O:7][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OC1CCCCC1
Product: Cc1cc(Nc2cc3ccccc3c(OC3CCCCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from cyclohexanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-cyclohexyloxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).