Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C1C(=O)N([I:36])C(=O)C1>C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:10]=[C:11]([I:36])[C:12]=1[O:13][CH3:14]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)c(F)c2)c1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2cc(F)c(OC)c(I)c2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
Sulfuric acid (3 mL) was added into a cold (ice bath) mixture of ethyl 1-(3-fluoro-4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 1.505 mmol) and NIS (339 mg, 1.505 mmol) in acetic acid (10 mL). The resulting mixture was stirred in an ice bath and was allowed to warm to ambient temperature overnight. The reaction was then heated in a 55° C. oil bath for 5 hrs. The crude mixture was combined with the reaction crude from an identical probe reaction (32 mg scale). The combined crude was poured into an ice/water mixture and extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 30%). Related fractions were pooled and evaporated to afford a colorless oil as the titled compound. LCMS calc.=457.98. found=459.06 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1F

Procedure:
The title compound, off-white solid (66 mg, 76%), MS (ISP) m/z=348.6 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [N:1]1([C:7]2[S:15][C:14]3[S:13](=[O:17])(=[O:16])[N:12](COCC[Si](C)(C)C)[CH2:11][C:10]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)([OH:26])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:1]1([C:7]2[S:15][C:14]3[S:13](=[O:17])(=[O:16])[NH:12][CH2:11][C:10]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)([OH:26])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1CC(O)(c2ccc3ccccc3c2)c2cc(N3CCOCC3)sc2S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)NCC(O)(c2ccc3ccccc3c2)c2cc(N3CCOCC3)sc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
6-(morpholin-4-yl)-4-(2-naphthyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-4-ol 1,1-dioxide (0.030 g, 0.055 mmol) was dissolved in THF (2.0 mL) and 1.00 M tetra-n-butylammonium fluoride in THF (0.549 mL, 0.549 mmol) was added. The solution was stirred at 40° C. overnight. The solvent was evaporated and the residue was purified using silica gel chromatography (12 g silica gel column, gradient 20% EA in hexane to 100% EA over 15 minutes) to give the product (14 mg, 55%). LCMS (FA) ES+: 417. 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.86-7.83 (m, 3H), 7.50-7.47 (m, 2H), 7.39-7.36 (m, 1H), 5.66 (s, 1H), 5.48 (s, 1H), 3.96 (d, 1H), 3.73-3.70 (m, 4H), 3.62 (d, 1H), 3.09-3.05 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22](O)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1([C:56]2[N:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH2:55][CH2:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.CC#N.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([NH:62][C:59]3[CH:60]=[N:61][C:56]([N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:57][CH:58]=3)=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Reactant: Nc1ccc(N2CCCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)Nc1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
A mixture of compound 39.3 (528 mg, 1.52 mmol, 1.00 equiv) and HBTU (635 mg, 2.28 mmol, 1.50 equiv) in DMF (30 mL) was stirred for 30 min at room temperature. To this was added 6-(pyrrolidin-1-yl)pyridin-3-amine (compound 41.2, 299 mg, 1.82 mmol, 1.20 equiv) and DIEA (50 mg). The resulting mixture was stirred overnight at 60° C. in an oil bath. After cooling to room temperature, the reaction mixture was diluted with 50 mL of EtOAc and washed with 2×30 mL of NH4Cl (aq., sat.) followed by 2×30 mL of sodium bicarbonate (aq., sat.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, Water with 50 mmol NH4HCO3 and CH3CN (10% CH3CN up to 32% in 3 min, up to 51% in 20 min, up to 100% in 1 min, down to 10% in 1 min); Detector, UV 220 NMnm. The fractions containing pure compound were combined and lyophilized to yield 50 mg (7%) of the title compound as a solid. m/z (ES+) 494 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18].[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])(O)=O.[Na+].O>COCCOC.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.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=2)[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18]
Reactant: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(CO)c2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 495 (0.039 g, 0.081 mmol) was dissolved in 1,2-dimethoxyethane (0.8 mL) in a screw cap vessel. 3-(Hydroxymethyl)phenylboronic acid (0.015 g, 0.097 mmol) and saturated aqueous NaHCO3 (0.4 mL) were added. Argon was blown over the mixture and Pd(PPh3)4 (0.005 g, 0.004 mmol) was added. The reaction mixture was stirred at reflux temperature under an argon atmosphere for 2 h. H2O and EtOAc were added and the water phase was extracted with EtOAc (×2). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.3, 159.1 (dd), 155.5 (dd), 147.8, 141.5, 140.6, 139.6, 138.3, 137.0, 135.3, 133.7, 131.8, 129.4, 129.1, 128.0, 126.3, 126.0, 125.6, 124.4 (dd), 124.3 (dd), 116.3, 112.8, 111.6 (dd), 104.9 (dd), 65.3, 20.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 65 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 65%). 1H NMR (300 MHz, CDCl3): δ 2.26 (s, 3H), 3.20 (s, 4H), 3.71 (s, 3H), 4.12-4.18 (m, 4H), 6.99-7.01 (m, 3H), 7.26-7.32 (m, 2H), 7.53-7.81 (m, 2H).
Reaction SMILES: FC(F)(F)C1C=CC(COC2C=CC(CO)=CC=2)=CC=1.C[O:22][C:23](=[O:55])[CH2:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([S:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=3)=[CH:38][CH:37]=2)=[CH:28][C:27]=1[CH3:54]>>[CH3:33][O:32][C:30]1[C:29]([S:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=3)=[CH:40][CH:41]=2)=[CH:28][C:27]([CH3:54])=[C:26]([CH:31]=1)[O:25][CH2:24][C:23]([OH:55])=[O:22]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: OCc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 14A. MS m/z 265 (M-Cl+1). Step 3. Preparation of {5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid methyl ester (Compound 14C)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C([O-])(O)=O.[Na+].[Cl:50][C:51]1[C:56]([CH3:57])=[C:55](I)[CH:54]=[CH:53][N:52]=1>O1CCOCC1.C(OCC)(=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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:26]([C:55]3[CH:54]=[CH:53][N:52]=[C:51]([Cl:50])[C:56]=3[CH3:57])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)ccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)ccnc1Cl
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a solution of EXAMPLE 30A (1.22 g) in dioxane (4 mL), and aqueous NaHCO3 (2 mL) was added 2-chloro-4-iodo-3-methylpyridine (505 mg), and tetrakis(triphenylphosphine)palladium(0) (115 mg). The mixture was stirred at 120° C. for 20 minutes in a Biotage Initiator microwave reactor. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3 times) and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which was loaded on a silica gel column and eluted with 20% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:15]([C:13]([OH:14])([CH:1]([CH3:3])[CH3:2])[CH2:12][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(O)(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with 1,3-diphenylacetone (210 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.0 mL, 1.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as white solid, mp=52−53° C. (241 mg, 95%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[S:16]1[C:20]([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=[N:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:20]2[S:16][N:17]=[CH:18][CH:19]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccns1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccns1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-isothiazol-5-yl-C-phenyl-methylamine hydrochloride (example 4.9).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1N)([CH3:3])[CH3:2].C(C1C=CC([N+]([O-])=[O:24])=CC=1N)C>>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[OH:24])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1N
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Product: CC(C)c1ccc([N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 2-isopropyl-5-nitroaniline (prepared using a similar procedure to that described by E. Dyszer et al., Przemysl. Chem. 42 (8) 433-5 (1963)), according to the method outlined in Description 51, as a dark brown oil (82%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH2:31][O:32][C:33](=[O:51])[C:34]3[CH:39]=[CH:38][C:37]([NH:40]C(OCC4C=CC=CC=4)=O)=[CH:36][CH:35]=3)=[O:28])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C)C>[Pd].C1COCC1>[NH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH2:31][CH2:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][C@H:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:15]([OH:17])=[O:16])=[O:51])=[CH:39][CH:38]=1
Reactant: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Nc1ccc(C(=O)OCCOC(=O)CC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
10% Palladium on charcoal (0.140 g) was added in one portion to a stirred solution of 24 (0.70 g, 1.02 mmol) in 1:1 mixture of isopropanol (10 mL) and THF (10 mL) under nitrogen atmosphere. The suspension was then stirred under hydrogen atmosphere at room temperature for 4 h. The solution was filtered through celite and concentrated under reduced pressure to obtain (S)-5-(2-(4-aminobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-5-oxopentanoic acid 25 (0.45 g, 96%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccc(Br)s4)n3n2)cc1
Yield: 24 %

Procedure:
Applying the Cyclization Procedure 1, using 5-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 48) (106 mg, 0.24 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.182 mL, 1.95 mmol), to afford 7-(5-bromo-2-thienyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (24 mg) as a yellow solid. MS m/z 416/418 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:13])=O>>[ClH:13].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](O)CCN
Agent: Cl
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (521.6 mg; 409.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 1.8 mL of thionyl chloride. The mixture was stirred at room temperature for 3 hours and then at 50° C. for 4 hours. Thereafter, the solvent was distilled off under reduced pressure to give 576.2 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 96.9% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Reaction time: 4 h

Procedure:
In a mixture of 30 ml of triethylamine and 60 ml of tetrahydrofurane, 7.0 g of the thus obtained 55% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 0.68 g of bis(triphenylphosphine)palladium (II) chloride and 0.18 g of cuprous iodide were added to the solution. A solution of 3.8 g of ethynyltrimethylsilane in 20 ml of triethylamine was added dropwise to the above solution, the resulting solution was heated to 68°-70° C. and stirred for 4 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using an ethyl acetate/hexane mixture as an eluent, and thus 4.2 g of 2-benzylthio-7-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[CH2:15][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)CN1CCNCC1)C1CCc2ccc(OC)cc2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 6a (3.87 g, 8.68 mmol) was dissolved in 40 ml of dichloromethane and 40 ml of trifluoroacetic acid was added. The mixture was stirred for overnight, at which time the solution was concentrated to dryness, dissolved in saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to yield 2.91 g (97%) of 7a as yellow wax, which was used in the next reaction. 1H NMR (400 MHz, CDCl3) 0.93-0.96 (t, 3H, J=12 Hz), 1.62 (m, 3H), 1.85-1.97 (m, 3H), 2.56 (m, 1H), 2.81-2.88 (m, 5H), 2.98-3.34 (m, 9H), 3.81 (s, 3H), 6.60 (s, 1H), 6.65-6.68 (d, 1H, J=12 Hz), 6.96-6.98 (d, 1H, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[CH3:37][NH:38][CH3:39].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([N:38]([CH3:39])[CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CNC
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)N(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 56.9 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added dimethylamine (2.0 M soln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (15 mg, 57%). LC-MS m/z 528 (M+H)+; 1H-NMR (MeOD) δ 2.23 (s, 3H), 2.78 (s, 6H), 3.06 (s, 3H), 3.15 (m, 5H), 3.55 (m, 2H), 4.22 (s, 2H), 7.19 (m, 3H), 7.34 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:16]=[C:15]([NH:17][C:18]([CH3:20])=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]=1[OH:21])[CH2:4][CH3:5])[CH3:2].[ClH:22]>C(O)C>[Cl:22][C:8]1[CH:7]=[C:6]2[C:20]([C:18]([NH:17][C:15]3[C:14]4[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=4[C:8]([OH:21])=[C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:16]=3)=[CH:2][CH:1]=[N:3]2)=[CH:14][CH:9]=1
Reactant: CCN(CC)Cc1cc(NC(C)=O)c2c(c1O)CCCC2
Reactant: Cl
Solvent: CCO
Product: CCN(CC)Cc1cc(Nc2ccnc3cc(Cl)ccc23)c2c(c1O)CCCC2
Yield: 90 %

Procedure:
A solution of 2 g of 2-diethylaminomethyl-4-acetamino-5,6,7,8-tetrahydro-I-naphthol, and 50 ml of concentrated hydrochloric acid in 200 ml of absolute ethanol was refluxed for 12 hours. Thereafter the solvent was distilled and the residue treated with ammonium hydroxide then extracted with ether. The etherial extract was washed with water and dried over magnesium sulphate. Then the ether was distilled to reside the amine. From this residual amine 6 g was mixed with 4 g of 4,7-dihchloroquinoline and few drops of conc. HCl in 50 ml of absolute ethanol and refluxed for 12 hours. Thereafter, the reaction mixture was cooled and diluted with water to double its volume then poured over a cold solution of ammonia. The formed precipitate was collected and washed with water. After drying, it weighed 9.2 g (90 % yield) of 4-(7-chloro-4-quinolylamino)-2-diethylaminomethyl-5,6,7,8-tetrahydro-I-naphthol (III). After recrystallization, it melted at 215°-217°C.