Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[N:10][CH2:9][CH:8]2[OH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCCl>[C:1]1([CH:7]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=3)=[N:10][CH2:9][CH:8]2[O:24][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CN=C(c2ccc(OC(F)(F)F)cc2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc(OC(F)(F)F)cc2)OC1c1ccccc1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
A mixture of (5RS, 6RS)-6-phenyl-2-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-4H-1,3-oxazin-5-ol (6 g) and phenyl isocyanate (2.4 g) in 1,2-dichloroethane (100 cc) is heated to a temperature in the region of 60° C. for 5 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 3.5 cm in diameter, eluting in 20-cc fractions with an ethyl acetate/cyclohexane mixture (30:70 by volume). Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in diisopropyl ether (5 cc). (5RS, 6SR)-6-Phenyl-5-phenylcarbamoyloxy-2-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 128° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@](O)(CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
To a solution of 0.041 g (0.001 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide (example 62 a) in 1.0 ml 2,2,2-trifluoroethanol was added 0.200 g (0.006 mol) cesium carbonate and the mixture was stirred at room temperature for 7 days. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.042 g (98% yield) of the title compound as white crystals melting at 96-97° C.
Reaction SMILES: B.CSC.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1.CSC>O1CCCC1>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][Cl:5])[CH:14]=[CH:13][N:12]=1
Reactant: N#Cc1cc(CCCCl)ccn1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1cc(CCCCl)ccn1

Procedure:
A solution of borane-dimethylsulfide (0.83 ml, 7.7 mmol) in 7 ml of tetrahydrofuran is added slowly to a refluxing solution of 4-(3-chloropropyl)-2-cyanopyridine (1.24 g, 6.9 mmol) in 7 ml of tetrahydrofuran while dimethylsulfide simultaneously distills off. The mixture is refluxed for 15 minutes after the addition is complete, cooled to 30° and 6 ml of 6N hydrochloric acid is added. After hydrogen evolution ceases, the mixture is refluxed for 30 minutes, cooled to 0° and saturated with solid sodium carbonate before extracting with methylene chloride (4×50 ml). The organic extracts are dried over sodium sulfate and evaporated to yield an oil which is filtered through 10 g of silica gel (1:1 EtOAc-MeOH) to yield 2-aminomethyl-4-(3-chloropropyl)pyridine as a yellow oil; NMR (CDCl3) 3.55 (t, 2H), 4.20 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:66][CH:65]([CH3:67])[C@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[C:62]([N:36]1[C@H:35]([C:33]2[NH:32][C:31]3[C:49]4[C:27]([CH:28]=[CH:29][C:30]=3[N:34]=2)=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:52]([CH3:54])[CH3:53])=[N:18][CH:17]=3)=[CH:24][CH:23]=2)=[CH:51][CH:50]=4)[C@@H:40]2[CH2:41][C@H:37]1[CH2:38][CH2:39]2)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (22 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (51.8 mg). LCMS-ESI+: calc'd for C44H54N8O5: 786.96 (M+); Found: 789.23 (M+H+).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][NH:6]2)[CH2:4][CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CC(C)([O-])C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:6]2[CH2:7][CH2:8][CH2:9][C:5]32[CH2:1][N:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3][CH2:4]3)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2)C1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2c2cccnc2)C1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate (1.00 g, ˜4.4 mmol), 3-bromopyridine (0.736 g, 4.66 mmol), potassium tert-butoxide (1.22 g, 10.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.155 g, 0.169 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.158 g, 0.254 mmol) and dry toluene (25 mL) was placed in a pressure tube under argon. The mixture was stirred and heated at 180° C. (bath temperature) for 8 h and cooled. Thin layer analysis indicated that very little conversion had taken place. A second charge, equal in quantity to the first, of all reagents except the tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate was added to pressure tube and the tube was returned to the bath for another 8 h. Again relatively little reaction seemed to have occurred, so a third charge of reagents was added and heating (at 180° C.) was continued for a third 8 h period. Water (20 mL) was added and the mixture was extracted with ethyl acetate (6×25 mL). The extracts were dried (K2CO3) and concentrated. Column chromatography of the residue on Merck silica gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone, gave 150 mg (˜11%) of light brown oil, after concentration of selected fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cc1
Yield: 93.7 %

Procedure:
Mix 3-chloro-4-fluorobenzaldehyde (3.28 g, 20.7 mmol), 4-hydroxybenzamide (3.12 g, 22.7 mmol), potassium carbonate (4.29 g, 31.0 mmol) and dimethylacetamide (80 mL) in a flask. Heat the reaction to 100° C. for 3 hours. Let cool to ambient (room) temperature and pour into water (200 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product (5.35 g, 94%). 1H NMR (DMSO-d6) 9.94 (s, 1H), 8.13 (d, J=1.7 Hz, 1H), 7.98 (bs, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.88 (dd, J=1.7 Hz, 8.5 Hz, 1H), 7.36 (bs, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:3]=1)[NH2:23]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from 4-(2-chloro-9-methyl-9H-purin-6-ylamino)-benzonitrile and hydrazine monohydrate.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC>C1COCC1.CCOCC.Cl>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([Si:12]([CH3:15])([CH3:14])[CH3:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2sccc12
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2c(Br)cccc2s1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of ˜80% pure 4-bromobenzothiophene (580 mg, 2.7 mmol) and chlorotrimethylsilane (0.70 mL, 5.4 mmol) in dry THF (10 mL) was cooled to −70° C. and 2 M LDA in 1:1 THF/heptane (1.35 mL, 5.4 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1.5 h and diluted with ether (80 mL) and 5% aq HCl (20 mL). The organic layer was separated, washed with sat'd aq NaHCO3 (20 mL) and dried over MgSO4. Removal of the solvent left 4-bromo-2-(trimethylsilyl)benzothiophene (740 mg, 95%) as an amber oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.C([O-])(=O)C.[Na+].[I:22]Cl>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[C:13]([I:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)cccc2o1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(I)c2o1
Reaction time: 30 h
Yield: 65.4 %

Procedure:
To a stirred solution of 40 g (18 mmol) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester and 4.4 g (54 mmol) sodium acetate in 20 ml acetic acid at room temperature was added dropwise 8.8 g (54 mmol) iodine monochloride and stirring continued for 30 h. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with 1 M aqueous sodium thiosulphate solution, then dried over sodium sulfate and concentrated in vacuo. Trituration in ether afforded 4.1 g (65%) (7-iodo-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as a white crystalline solid. ES-MS m/e (%): 349 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(#N)C.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:14]=4)[CH2:25][CH2:26]3)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1ccc2cc(C3CCN(CCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-2-(4-indolyloxy)ethane, 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 29% overall yield as a white solid. mp. 119°-120° C. FDMS m/e=370 (M+ of free base).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])(=O)C.[K+].C(O)C>[Cl-].[Na+].O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10]
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Reactant: COc1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(N)c1

Procedure:
1-Bromo-2-fluoro-4-methoxybenzene (750 mg, 3.66 mmol), [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (856 mg, 4.39 mmol), potassium acetate (3.66 mL, 2M aq, 7.32 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (299 mg, 10 mol. %) and ethanol (30 ml) were heated in an 80° C. oil bath for 3 hours. Reaction crude was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark oil. This oil was purified by SiO2 (Biotage HorizonFlash system, 40+M cartridge, 0-25% EtOAc/hexanes, v/v) to afford the title compound as a yellow crystalline solid. LCMS calc.=275.10; found=276.09 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)=[O:4].[H-].[K+].[CH3:23]I>C1COCC1.CCOCC>[CH3:20][N:2]([CH3:1])[C:3]([S:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:19])[CH:13]([CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)CCC(=O)c1ccc(SC(=O)N(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC(C)C(=O)c1ccc(SC(=O)N(C)C)cc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
The compound from Step D, (10.0 g, 33.9 mmoles) was dissolved in THF (100 ml) and added dropwise to a stirred mixture of potassium hydride (1.6 g, 40.7 mmoles) in THF (10 ml) at -45° C. The reaction mixture was warmed to 0° to initiate the reaction, then cooled to -45° C. After 30 minutes, the reaction mixture was warmed to 0° C., and stirred for 10 minutes A solution of methyl iodide (3.17 ml, 50.9 mmoles) in THF (10 ml) was added slowly to the cold solution. The mixture was stirred at 0° for one hour. The reaction mixture was diluted with ether, washed with water, brine, dried and evaporated to yield an oil which was purified by HPLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:10]([F:12])([F:13])[F:11])[C:14]([F:16])([F:17])[F:15]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a dichloromethane (10 mL) solution of tert-butyl 4-(5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-ylamino)benzoate (Preparation 258, 220 mg, 0.47 mmol) was added trifluoroacetic acid (2 mL) at room temperature, and the reaction stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography eluting with acetonitrile:water (5:95 to 95:5) to yield the title compound as a pale yellow solid (116 mg, 60%).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([S:7]([OH:10])(=[O:9])=[O:8])=[C:4]([C:11]([O-:13])=[O:12])[CH:3]=1.[K+:14].[OH-].[K+]>O>[S:7]([C:5]1[S:6][CH:2]=[CH:3][C:4]=1[C:11]([O-:13])=[O:12])([OH:10])(=[O:8])=[O:9].[K+:14]
Reactant: O=C([O-])c1cc(Cl)sc1S(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccsc1S(=O)(=O)O

Procedure:
40 g. of potassium 5-chloro-2-sulfothiophene-3-carboxylate are dissolved in 24 g. of caustic potash dissolved in 400 ml. of water, stirred with 4 g. of activated charcoal, and filtered. 2 g. of palladium/activated charcoal (10% Pd) are then added and the mixture is hydrogenated at room temperature and at an initial pressure of approximately 1 atmosphere until no more hydrogen is taken up. The catalyst is removed by filtration. The filtrate is concentrated by evaporation to 35 ml., and acidified with concentrated HCl to a pH of 1. The precipitate that separates out is redissolved by heating. The resulting solution is cooled to 5°, and the precipitated product is suction filtered without rewashing and dried in vacuo to constant weight, and potassium 2-sulfothiophene-3-carboxylate is obtained.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C(Cl)Cl.O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[S:7][CH:8]=1
Reactant: OCc1cc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), (4-bromo-thiophen-2-yl)-methanol (3.97 g, 20.57 mmol) was dissolved in dry CH2Cl2 (50 mL). tert-Butyldimethylsilyl chloride (3.59 g, 22.63 mmol) was added at rt followed by imidazole (1.56 g, 22.63 mmol). The reaction mixture was stirred at rt for 1 h. Water was added, the layers were separated and the org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (hept) gave the title compound as a colorless oil. TLC:rf (100:1 hept-EA)=0.44. LC-MS-conditions 02: tR=1.21 min.
Reaction SMILES: CS(C1C=CC(C2C=CC3[N:15](N=C(N)N=3)C=2)=CC=1)(=O)=O.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH2:15])=[CH:23][CH:24]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: Nc1ccc(N2CCOCC2)cc1

Procedure:
6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-phenyl)-morpholine (51.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.011 g, 14%). MP=>300° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H), 9.28 (s, 1H), 8.09 (d, J=7.7 Hz, 2H), 8.03-7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 3.77-3.71 (m, 4H), 3.28 (s, 3H), 3.05-3.00 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH3:40])[C:19]([NH:21][CH2:22][C:23]1[S:27][CH:26]=[C:25]([N:28]2[C:32]([C:33](O)=[O:34])=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[N:29]2)[CH:24]=1)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:33]([C:32]1[N:28]([C:25]2[CH:24]=[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[CH3:40])[S:27][CH:26]=2)[N:29]=[C:30]([C:36]([F:37])([F:39])[F:38])[CH:31]=1)=[O:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Reactant: Cc1ccccc1CN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a solution of 2-methylbenzylamine (0.037 mL, 0.295 mmol) and compound 7 (0.091 g, 0.197 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.075 g, 0.394 mmol) followed by DMAP (9.62 mg, 0.079 mmol). The reaction was left to stir for 16 hours at room temperature. The solvent was then removed on the rotary evaporator and the brown material was purified by silica gel chromatography with a 12M Biotage column and a gradient of 0-5% methanol in dichloromethane to give 61.3 mg of a yellow crust. The sample was further purified by preparative HPLC (C18 Aquasil 20×250 mm; 40-85% methanol in water in 45 minutes at 10 mL/min) to afford compound 15a (34.4 mg, 31%) as a white crust. LRMS (ESI): calc. 565.2; found 466.1 (MH-Boc)+, 588.2 (MNa)+.
Reaction SMILES: [OH-].[K+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[OH:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:23])[CH:19]=[C:20]([O:14][C:8]2[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])[N:21]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1cc(Oc2c(Cl)cccc2Cl)nc(Cl)n1
Yield: 55.1 %

Procedure:
Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solution of 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). The mixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added. The mixture was stirred overnight at 60° C. The reaction was quenched with NaOH 1N solution. The aqueous layers were extracted with EtOAc several times and then the organic layers were combined and washed with NaOH 3N and saturated NaCl, dried and concentrated. The residue was recrystallized from CH2Cl2/hexane. The precipitate was filtered off and dried, yielding 5.98 g 2,4-dichloro-6-(2,6-dichlorophenoxy)pyrimidine (55%) (interm. 12).