Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18][CH3:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+]>O>[Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18][CH3:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(SC)c(OCCOC)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1c(SC)ccc(C(=O)O)c1Br
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Ethyl 2-bromo-3-(2-methoxyethoxy)-4-methylsulphenyl-benzoate (24.3 g) was added to a solution of potassium hydroxide (9.1 g) in water (25 ml) and industrial methylated spirits (300 ml). The resultant mixture was heated at reflux for 4 hours and then allowed to cool to room temperature overnight. The mixture was evaporated and the residue dissolved in water and washed with ether. The aqueous layer was acidified to pH 1 with 2M HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-bromo-3-(2-methoxyethoxy)-4-methylsulphenyl benzoic acid (19.4 g) as a white solid, NMR (CDCl3) 2.2(3H,s), 3.25(3H,s), 3.6(2H,t), 3.8(2H,t), 7.0(2H, m).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[O:66]=[C:67]([N:80]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:109]=[CH:108][C:107]([C:110]6[NH:114][C:113]([C@@H:115]7[CH2:119][CH2:118][CH2:117][NH:116]7)=[N:112][CH:111]=6)=[CH:106][CH:105]=5)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[CH2:87][C:82]2([O:86][CH2:85][CH2:84][O:83]2)[CH2:81]1)[C@@H:68]([NH:75][C:76](=[O:79])[O:77][CH3:78])[CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1.Cl>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:114][C:110]([C:107]2[CH:108]=[CH:109][C:104]([C:99]3[CH:98]=[CH:97][C:96]4[C:101](=[CH:102][CH:103]=[C:94]([C:91]5[NH:90][C:89]([C@@H:88]6[CH2:87][C:82]7([O:83][CH2:84][CH2:85][O:86]7)[CH2:81][N:80]6[C:67](=[O:66])[C@@H:68]([NH:75][C:76]([O:77][CH3:78])=[O:79])[CH:69]6[CH2:74][CH2:73][O:72][CH2:71][CH2:70]6)=[N:93][CH:92]=5)[CH:95]=4)[CH:100]=3)=[CH:105][CH:106]=2)=[CH:111][N:112]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-oxo-2-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt. MS (ESI) m/z 923.83 [M+H]. (73 mg, 77%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].O>C1COCC1.CC(C)([O-])C.[K+]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:16][CH2:15][CH2:14][CH2:13][NH2:12])=[N:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: NCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCOc1ccc(C(F)(F)F)cn1
Temperature: 0 °C

Procedure:
2-Fluoro-5-trifluoromethylpyridine (1.831 g, 11 mmol) was dissolved in anhydrous THF (15 mL) with stirring under nitrogen and cooled to 0° C. in an ice bath. To this was added dropwise over 30 minutes a solution of 3-amino-1-propanol (0.76 mL, 10 mmol) in anhydrous THF (15 mL) and 1M potassium tert-butoxide in THF (10 mL, 10 mmol). The yellow solution was allowed to stir and warm to room temperature in the ice bath overnight. The reaction mixture was poured into water (75 mL) and extracted with ether (2×50 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and evaporated under vacuum to a yellow liquid, which was nearly pure by NMR and MS, and was used as such without further purification.
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH3:14])[CH:4]([OH:13])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])#[N:2].[OH-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:15])([CH3:14])[CH:4]([OH:13])[CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(O)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C#N)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To the reaction mixture obtained in Example 2 were added 10% aqueous sodium hydroxide solution (113.8 g) and methanol (20 mL), and the mixture was stirred at room temperature overnight. The disappearance of tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate was confirmed by gas chromatography (GC). Toluene (50 mL) was added and the mixture was stirred and then partitioned to remove the toluene layer. 20% Aqueous hydrochloric acid solution (67.5 g) was added to the aqueous layer to adjust its pH to an acidic one (ca. pH 1-2) and the mixture was extracted twice with ethyl acetate (150 mL). The ethyl acetate layer was concentrated under reduced pressure to give 4-cyano-3-hydroxy-4-methylpentanoic acid (19.9 g) as an oil. When left standing, this oil crystallized. The yield was 89% relative to tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:42](=[O:43])[N:41]([CH3:45])[CH3:40])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)N(C)C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 112.8 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TEA (0.18 mL, 1.30 mmol) followed by dimethylcarbamyl chloride (0.10 mL, 1.04 mmol). The reaction mixture was allowed to warm to ambient temperature. After 6 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 88 (612 mg, 100%) as a white foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.04 (q, J=9.0, 18.3 Hz, 1H), 6.88 (br s, 1H), 6.75-6.67 (m, 1H), 6.61-6.56 (m, 1H), 4.79-4.51 (m, 2H), 4.31 (d, J=5.7 Hz, 1H), 4.08-4.01 (m, 1H), 3.99-3.94 (m, 1H), 3.81-3.72 (m, 1H), 3.54-3.49 (m, 1H), 3.41-3.25 (m, 2H), 2.85-2.79 (m, 9H), 2.05-2.03 (m, 2H), 1.49-1.42 (m, 9H), 1.31 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: O=Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethylcarbamate (131 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60° C. for 3 hours. After diluting with DCM (20 mL), the reaction was filtered through Celite®, concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/H2O to provide (R)-tert-butyl 2-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 86.6% yield) as yellowish solid. MS (apci) m/z=370.4 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[NH:12][C:11](=[S:39])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Product: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-2H-1,4-benzodiazepin-2-thione (IIn) was prepared by reacting 0.00089 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-2H-1,4-benzodiazepin-2-one (lactam In) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=430.
Reaction SMILES: [O:1]=[C:2]1[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.I[CH:28]([CH3:30])[CH3:29].O>CN(C=O)C>[CH3:29][CH:28]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:2]1=[O:1])[CH3:30]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
A mixture of tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1480 mg) and 2-iodopropane (714 mg) in DMF (5 mL) was stirred at 60° C. for 4 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (570 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (59 mg, 0.59 mmol), acetic acid (0.053 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 372.0 [M]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[C:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(Cl)(=O)C([Cl:39])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[C:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:13]([CH:17]=1)[C:14]([Cl:39])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)cc(OCc2ccccc2)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)Cl)cc(OCc2ccccc2)c1O[Si](C)(C)C(C)(C)C
Yield: 91.7 %

Procedure:
A solution of 5-benzyloxy-3,4-di-t-butyldimethylsiloxybenzoic acid (1 g, 2 mmol) in 46 mL of benzene was added to a solution of NaH (80 mg, 2 mmol) in 2 mL of benzene. The resulting solution was stirred with oxalyl chloride (0.9 mL, 10 mmol) under Ar for 20 h. Removal of solvent afforded 0.93 g (91%) of 5-benzyloxy-3,4-di-t-butyldimethylsiloxybenzoyl chloride as a yellow solid.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[C:7]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:8]2=O)[CH:3]=[CH:2]1.O.[NH2:19][NH2:20]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:15](=[O:16])[NH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C2=C(CCCC2)C(=O)C1=C1C=CNC=C1
Solvent: O
Product: O=c1[nH]nc(Cc2ccncc2)c2c1CCCC2

Procedure:
A mixture of 0.773 g (3.4 mmol) 2-[4(1H)-pyridinylidene]-4,5,6,7-tetrahydro-inden-1,3-dione and 5 ml hydrazine hydrate is heated for 4 h under reflux. The title compound is obtained after cooling to 0° C., filtration, washing of the filter residue with water, then ether, and drying under HV (8 h, 100° C.); m.p. 193-194° C.; ESI-MS: (M+H)+=242.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH2:19])[CH:14]=[CH:15][C:16]=1[F:17].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH:19][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C1CCCC(=O)O1
Reactant: NCc1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of glutaric anhydride (342 mg, 3 mmol), [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride salt (721.5 mg, 3 mmol), and diisopropyl ethyl amine (2 mL) in THF (50 mL) was stirred at room temperature for 1 hour. It was concentrated, mixed with 4% HCl (50 mL) and extracted with EtOAc (50 mL, 2×). The combined organic extracts were dried and concentrated to provide the captioned product (920 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:35])[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:35][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Cn1nnnc1-c1cc(N)cc(C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Cn1nnnc1-c1cc(Nc2ncc(F)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc(C2CC2)c1
Yield: 41.6 %

Procedure:
2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (90 mg, 0.31 mmol) was treated with 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine (80 mg, 0.37 mmol) and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol) in isopropanol (5 mL) and heated at reflux, in a loosely capped vial, overnight. The solvent evaporated, over the course of the reaction. 2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine remained in the reaction mixture. An additional equivalent of 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine was added, along with more isopropanol. The reaction was allowed to heat at reflux for an additional 8 hours. This process was repeated until the 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine was consumed, 4 days later. The resulting residue was purified by column chromatography, on silica gel, eluting with methanol:methylene chloride (1:99) followed by 2M ammonia in methanol:methylene chloride (2:98), to yield N2-(3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (60 mg, 42% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[CH:13]=[N:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[CH:13]=[N:14][CH:15]=1)[CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cn1c(=O)oc2ccc(-c3cncc(CNCc4ccccc4)c3)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN(Cc1ccccc1)Cc1cncc(-c2ccc3oc(=O)n(C)c3c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(5-(Benzylamino-methyl)-pyridin-3-yl)-3-methyl-3H-benzooxazol-2-one (crude from step 2, ˜0.39 mmol) and Pd(OH)2 (20 mg, 10%) in ethanol (10 mL) and acetic acid (0.5 mL) was stirred under 1 atmosphere of H2 at room temperature for 48 h. After filteration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-5%) and yielded yellow solid (3 mg), ESI-MS m/z: 387.9 [M+1]+, Retention time 1.45 min; 1HNMR (CDCl3, 400.342 MHz) δ 1.48 (t, J=7.2 Hz, 3H), 3.05 (s, 2H), 3.48 (s, 3H), 4.23 (s, 2H), 4.05-4.27 (m, 2H), 7.21 (s, 1H), 7.23 (5, 1H), 7.40-7.43 (m, 3H), 7.62-7.64 (m, 2H), 7.83 (s, 1H), 8.52 (5, 1H), 8.85 (d. J=1.84 Hz, 1H), 9.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyl-oxy)piperidine-1-carboxylate in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), Rt=3.81 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccc(F)cc3F)c3ncccc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 ml of phosphoryl chloride were added to 2.74 g (6.221 mmol) of the compound from Example 77A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 430 ml of acetonitrile and, with ice cooling, stirred into 260 ml of concentrated ammonia solution (33% in water). The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was stirred with ethyl acetate and diethyl ether. A solid was filtered off with suction and then washed with diethyl ether and ethyl acetate. Drying under high vacuum gave 2.13 g of the title compound in a purity of 94% (79% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]=CN(C)C)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:22]([C:16]2[C:15]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:35]([F:37])([F:38])[F:36])[CH:4]=3)(=[O:10])=[O:9])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=2)=[O:23])[CH:29]=[CH:28][N:27]=1
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C(=O)c2ccnc(N)c2)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (23 mg, mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH—CH2Cl2) to afford N-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoro methyl-benzenesulfonamide (12 mg) in 63% yield. 1H NMR (400 MHz, CDCl3) δ 10.75 (s, 1H), 8.24 (s, 1H), 8.18 (m, 1H), 8.07 (dd, 1H), 7.95 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.15 (s, 1H), 6.95 (d, 1H), 2.25 (s, 3H); ESMS m/z (relative intensity): 471.0 (M+H)+ (100).