Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CO.[Cu]>[Br:1][C:2]1[CH:7]=[C:6]([O:10][CH3:9])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
A mixture of 3,5-dibromopyridine (20.00 g, 84.42 mmol), sodium methoxide (11.40 g, 211.06 mmol), and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) in dry methanol was heated in a sealed glass tube at 150° C. for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 9.40 g (59.5%) of a colorless oil, which tended to crystallize upon cooling.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.N1CCCC1.[CH2:14]([OH:17])[C:15]#[CH:16]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:16]#[C:15][CH2:14][OH:17])=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCNC1
Product: Nc1ccc(C#CCO)cn1
Temperature: 80 °C

Procedure:
2-Amino5-bromopyridine (7-1), 10.0 g (57.8 mmol) was stirred in pyrrolidine (96.5 mL, 1.16 mol, 20 equiv) in a flame dried round bottom flask under argon. Propargyl alcohol (10.1 mL, 173 mmol) and tetrakis triphenylphosphine palladium(0) (1.34 g, 1.16 mmol) were added and the solution was degassed 3×by alternating vacuum/Ar. Heat to 80° C. After 18 h the bulk of the pyrrolidine was removed in vacuo and the residue was diluted with water. Extract with CH2Cl2 three times, and the extracts were dried over Na2SO4, filtered and concentrated to provide impure product. The aqueous layer was further extracted ten times with CH2Cl2/nBuOH (95:5). The extracts were dried over Na2SO4, filtered and concentrated. The two samples were combined and were purified in two batches by flash column chromatography (gradient: CH2Cl2 to CH2Cl2/MeOH, 90:10). The product was triurated with ice cold CH2Cl2, filtered, and washed with ice cold CH2Cl2. Afforded the titled compound as a pale yellow solid. 1H NMR (CD3OD) δ7.96 (d, 1H, J=2.2 Hz), 7.45 (dd, 1H, J=2.4, 8.8 Hz), 6.51 (d, 1H, J=8.8 Hz), 4.36 (s, 2H).
Reaction SMILES: ClC1C=CC=C(Cl)[C:3]=1[N:9]1C=C2C(NC3C=C(NC)N=CN=3)=NC=CC2=N1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[C:40]3=[CH:41][N:42]([C:44]4[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=4[Cl:51])[N:43]=[C:39]3[CH:38]=[CH:37][N:36]=2)[CH:31]=[C:30]([CH3:52])[N:29]=1.CN>>[Cl:51][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]([Cl:50])[C:44]=1[N:42]1[CH:41]=[C:40]2[C:35]([NH:34][C:32]3[CH:31]=[C:30]([CH3:52])[N:29]=[C:28]([NH:9][CH3:3])[N:33]=3)=[N:36][CH:37]=[CH:38][C:39]2=[N:43]1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(Cl)n1
Reactant: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Agent: CN
Product: CNc1nc(C)cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)n1
Yield: 33 %

Procedure:
Following the procedure described for N-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-N′-methylpyrimidine-4,6-diamine, (2-chloro-6-methylpyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]amine and methylamine were reacted to afford the title compound as a yellow solid (24 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 9.16 (s, 1H), 7.94 (d, J=6.4 Hz, 1H), 7.81-7.80 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 7.65 (s, 1H), 7.15 (dd, J=6.4, 1.0 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.25 (s, 3H). LCMS (Method B): RT=2.90 min, m/z: 400 [M+H+].
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[CH2:27][CH2:28][CH3:29]>O1CCOCC1.C(O)C>[CH3:29][CH2:28][C:27]([C:18]1[C:17]([O:16][CH3:15])=[CH:22][C:21]([O:23][CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:6]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1cc(OC)c(OC)cc1OC
Solvent: CCO
Solvent: C1COCCO1
Product: CCC(=O)c1cc(OC)c(OC)cc1OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of DDQ (3.06-4.09 g) in dioxane (40 mL) was added dropwise over a period of 10 min to a ice cold and well stirred solution of 2,4,5-trimethoxyphenylpropane (1.89 g, 0.009 mol) in wet dioxane or ethanol (55 mL) and the resulting mixture was stirred at room temperature for over night. The precipitate was filtered and further washed twice with dioxane. The combined dioxane layer was evaporated and mixture was poured into water and extracted with dichloromethane (3×70 mL). The combined organic layer were washed with brine (3×15 mL) and dried over sodium sulphate. The residue obtained on evaporation of the solvents was chromatographed on silica gel column using hexane-ethyl acetate mixture with increasing proportion of ethyl acetate upto 40% to afford viscous liquid which was crystallized from ethylacetate/hexane to afford 1.19 g (59%) of white crystals of isoacoramone. The spectral data was found similar as mentioned above in Example III.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH2:48])=[CH:47][C:42]=2[N:41]=[N:40]1.Cl>CCO>[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH:48][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4[nH]nnc4c3)n2)c1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 74.5 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (103 mg, 0.223 mmol.) in 1 mL of EtOH/0.5 mL of DMF, 1H-1,2,3-benzotriazol-5-amine (32 mg, 0.245 mmol) and 5 μL of conc. HCl, the reaction contents were heated to 80° C. After heating for 18 h, the reaction mixture was cooled to rt and partitioned between DCM and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with DCM (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo. Addition of TFA, followed by titration with Et2O afforded the desired product as a yellow solid 93 mg, 63% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.91 (s, 1H); 9.91 (s, 1H); 8.54 (d, J=7 Hz, 1H); 8.52-8.49 (m, 2H); 8.31 (d, J=5 Hz, 1H); 7.99 (s, 1H); 7.82 (t, J1=10 Hz, 2H); 7.60-7.53 (m, 2H); 7.50-7.45 (m, 2H); 7.37 (d, J=8 Hz, 1H); 7.23 (t, J=9 Hz, 2H); 7.13 (t, J=7 Hz, 1H); 6.55 (d, J=5 Hz, 1H). HRMS calculated C30H20F2N9O [M+H]+ 560.1759, found 560.1763.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13]>>[CH3:10][N:11]([CH3:15])[C:12]([O:2][N:1]=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)=[O:13]
Reactant: CN(C)C(=O)Cl
Reactant: CC1=NCCSC1=NO
Product: CC1=NCCSC1=NOC(=O)N(C)C

Procedure:
2-Oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime is reacted with dimethylcarbamoyl chloride as described in Example 2 to yield 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine O-(dimethylcarbamoyl) oxime, m.p. 64°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[C:12]([NH:15][NH2:16])(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:15][NH:16][C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1])=[S:11])(=[O:14])[CH3:13]
Reactant: Cc1ccc(Cl)c(N=C=S)c1
Reactant: CC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)NNC(=S)Nc1cc(C)ccc1Cl

Procedure:
One tenth mole, 18.3 g., of 2-chloro-5-methylphenylisothiocyanate and 11.0 g. (0.15 mole) of acetylhydrazine were refluxed for 7 hours in 500 ml. of THF. After cooling, the insoluble product was collected by filtration. The crude product was collected by filtration. The crude product was washed with water, filtered and dried. The yield was 25 g. of 1-acetyl-4-(2-chloro-5-methylphenyl)-3-thiosemicarbazide, m.p. about 145°-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:42]([NH:44][CH2:45][CH3:46])[CH3:43]>C(O)(=O)C.ClCCCl>[CH2:42]([N:44]([CH2:45][CH3:46])[CH2:26]/[CH:25]=[CH:24]/[C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:43]
Reactant: CCNCC
Reactant: Nc1ncc(/C=C/C=O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12

Procedure:
A mixture of Example 360B (30 mg, 0.080 mmol), sodium triacetoxyborohydride (35 mg, 0.16 mmol), 1 drop of acetic acid, and diethylamine (12 mg, 0.166 mmol) in 1,2-dichloroethane (2 mL) was stirred for 2 hours at ambient temperature. The mixture was concentrated and the residue was purified by reverse phase chromatography followed by lyophilization to provide the desired product as the acetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (s, 1H), 7.55 (s, 1H), 7.44 (m, 4H), 7.20 (t, 1H), 7.11 (m, 4H), 6.67 (d, 1H), 6.22 (m, 1H), 5.55 (br s, 2H), 3.28 (d, 2H), 2.52 (q, 4H), 1.87 (s, 3H), 1.00 (t, 6H); MS m/e 430.4 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][NH:4]2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: CN1CCNCC1
Product: CN1CCN(C[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and 1-methylpiperazine (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 112. MS(ESI+) m/z 246.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Ni].CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1)C1CCOCC1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(CCC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1)C1CCOCC1
Reaction time: 3 h

Procedure:
A reaction mixture of 60 mg (0.13 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-{[methyl-(tetrahydropyran-4-yl)amino]methyl}phenyl)acrylamide and 20 mg of Raney nickel in 10 mL of DMF is hydrogenated for 3 hours at 50 psi and ambient temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (20:1:0.1)). Yield: 22 mg (29% of theory); melting point: 167° C.-173° C.; C28H31ClN2O2 (M=463.01); calc.: molecular ion peak (M+H)+: 463/65 (Cl); found: molecular ion peak (M+H)+: 463/65 (Cl).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>>[Cl:14][C:15]1[N:16]=[C:17]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[CH:18]=[N:19][CH:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 36.9 %

Procedure:
In a procedure analogous to Example 1, reaction of 4-morpholinoaniline (2.15 g, 12.1 mmol) and 2,6-dichloropyrazine (0.756 g, 5.03 mmol) furnished the product (0.54 g, 37%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[C:15]([NH2:17])=O.B.CSC>C1COCC1>[NH2:17][CH2:15][C@H:3]1[C@@H:2]([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1
Reactant: NC(=O)[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NC[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: 80 °C

Procedure:
A solution of (cis)-4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxamide (0.7 g, 3 mmol) in THF (6 ml) was treated with a borane-methyl sulphide complex (2M solution in THF, 3.3 ml). The reaction mixture was heated at 80° C. for 1300 s under microwave irradiation conditions. This was repeated twelve times and then the reaction mixtures were combined and the solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and aqueous ammonia gradient (20% methanol/dichloromethane-20% 2M ammonia in methanol/dichloromethane) to provide 4.6 g of the desired pure compound and 1.1 g of less pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc(Cl)cc1
Temperature: 125 °C
Yield: 93.5 %

Procedure:
A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96%) as a white solid. UV λmax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm−1; MS (El ) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32]CC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][OH:36]>C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30](=[O:32])[NH:35][OH:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: NO
Solvent: CC(C)O
Product: O=C(COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1)NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (144 mg, 0.30 mmol, 1.0 eq.) in isopropanol (1.5 mL), hydroxylamine (50% w/w aqueous solution, 1.5 mL) was added. The ice bath was removed and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated to half and water (5 mL) was added. The resulting suspension was filtered, washed with water and dried under hv to give the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 36 %

Procedure:
Prepared from VII and 4-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 36%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2225, 2218, 1722, 1628, 1590, 1562, 1495, 1461, 1387, 1261, 1228, 1132, 966, 847, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 7.77 (m, 3H), 7.40 (d, 2H, J=9.0 Hz); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0612.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].[OH:6][C:7]([C:16]([F:19])([F:18])[F:17])([C:12]([F:15])([F:14])[F:13])[C:8](OC)=[O:9].[Cl-].[NH4+]>O1CCCC1>[CH3:3][CH:2]([CH3:4])[CH:8]([OH:9])[C:7]([C:12]([F:13])([F:14])[F:15])([OH:6])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)Cl
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A flask was charged with 9.5 g of magnesium and 300 ml of tetrahydrofuran, to which 35.0 g of isopropyl chloride was added dropwise at 50° C. After the completion of dropwise addition, the contents were stirred for one hour at 60° C., and 22.6 g of methyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate was added dropwise below 50° C. The mixture was stirred for one hour at room temperature, after which an ammonium chloride aqueous solution was added. This was followed by ordinary work-up and vacuum distillation, obtaining 20.2 g of the target compound (yield 84%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:4]1[S:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])=[N:6][CH:5]=1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: Nc1ncc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-amino-5-bromothiazole (1220 mg, 6.81 mmol) in dichloromethane (10 ml) was added triethylamine (1.235 ml, 8.86 mmol) and 4-dimethylamino pyridine (83 mg, 0.681 mmol), followed by addition of 5-chloro-2-methoxybenzoyl chloride (1397 mg, 6.81 mmol) and stirred overnight. The reaction was concentrated and water was added to the residue. The mixture was sonicated and filtered to obtain the title compound as off-white solid (1.56 g, 66%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.88 (m, 3H) 7.23 (d, J=8.81 Hz, 1H) 7.58-7.67 (m, 3H) 12.32 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:23]=[C:22]([NH2:24])[S:21][N:20]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([NH:24][C:22]1[S:21][N:20]=[C:19]([CH3:18])[N:23]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1nsc(N)n1
Product: Cc1nsc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)n1

Procedure:
C9a was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoic acid C7c and 3-methyl-1,2,4-thiadiazol-5-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:51]=[CH:50][C:28]([C:29]([NH:31][CH:32]([CH:37]5[CH2:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]5)[C:33]([O:35][CH3:36])=[O:34])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:51]=[CH:50][C:28]([C:29]([NH:31][CH:32]([CH:37]5[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]5)[C:33]([O:35][CH3:36])=[O:34])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 3-(1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (85 mg) in DCM (5 mL) was added TFA (0.357 mL). The mixture was stirred at room temperature for 4 hours. All the solvents were removed under vacuum to give methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (70 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 8-(tert-butoxycarbonylamino)-2-naphthol, as described above in Step A, (35 g, 0.135 mol), tert-butyldiphenylsilyl chloride (40.9 g, 0.149 mmol), and imidazole (18.4 g, 0.270 mmol) in dry, degassed DMF (300 mL) was stirred, under argon, at 50° C. for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (500 mL) and EtOAc (1 L). The aqueous layer was extracted further with EtOAc (300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane −25% to 45% CH2Cl2 to yield the desired product as a pale solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH2:6]2.O1CCCC1.[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12](=[O:14])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:11]=1)[NH:8][C:7](=[O:15])[CH2:6]2
Reactant: COc1cc2c(c(C(=O)O)c1)NC(=O)C2
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(C(=O)c3ccccc3)c1)NC(=O)C2
Reaction time: 2 h

Procedure:
A suspension of 1.0 g. (4.9 mole) of 5-methoxy-7-carboxyindolin-2-one in 20 ml. of tetrahydrofuran was treated dropwise with 12 ml. of commercially prepared phenyllithium solution (2.3 molar ether: benzene; 0.28 moles). After stirring for two hours the reaction mixture was poured into water and extracted several times with ethyl ether and benzene. The combined extracts were washed with water, dried over sodium sulfate and concentrated using a rotary evaporator to a solid residue which on recrystallization from acetone-water gave 259 mg. (21%) of a yellow powder which melted at 154° C.