Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH2:26][C:27]#[N:28])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[C:22]([CH2:26][C:27]#[N:28])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: N#CCc1[nH]nc(N)c1C#N
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3nc(CC#N)c(C#N)c3n2)ccc1Cl
Yield: 52.7 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (74 mg, 0.5 mmol) according to general procedure B yielded the title compound as a light yellow solid (99 mg, 53%). MS (ISP) 376.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([CH2:12][Br:17])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Temperature: 25 °C
Yield: 112.5 %

Procedure:
To a solution of 12.0 g (281 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 84 mL carbon tetrachloride was added 7.59 g (42.7 mmol) of N-bromosuccinimide and 0.310 g (1.28 mmol) of benzoyl peroxide. This was heated to reflux for 40 minutes and then cooled to room temperature. To the cooled solution was added 170 mL petroleum ether and the solution was filtered and concentrated in vacuo to give 17.3 g of 2-bromo-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[S:8])[NH:4][CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:11]=[C:12]([O:18][C:19]2[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13]([C:16]#[N:17])=[N:14][CH:15]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([S:8][C:10]2[CH:11]=[C:12]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc[nH]c1=S
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1Sc1cnc(C#N)c(Oc2cccnc2C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
3-Methylpyridine-2(1H)-thione (0.906 g, 7.24 mmol) and 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.89 mmol) were dissolved in DMF (12 mL) and the mixture was cooled to 0° C. Sodium hydride (95%; 0.183 g, 7.24 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was poured into water (100 mL), stirred for 30 minutes, then filtered to afford a solid which was purified over silica gel (2:3 hexanes:ethyl acetate). Concentration of the second UV active fraction to elute afforded 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile (1.40 g, 4.19 mmol, 60.7% yield) as a pale yellow/off white powder/crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:19]1[CH:18]=[N:17][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:21][N:20]=1)=[O:23])([CH3:39])[CH3:35]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 5-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (96 mg, 0.29 mmol) and TBTU (103 mg, 0.32 mmol) in DMF (1.5 mL) was added DIPEA (250 μL, 1.46 mmol). Then isopropylamine (27 μL, 0.32 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (53 mg, 49%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=371.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[S:15]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:18])(=[O:17])[NH2:16].C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[N:5][NH:6]2)=[C:2]([C:23]2[CH:24]=[C:19]([S:15]([NH2:16])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)cc3[nH]ncc23)c1
Temperature: 140 °C
Yield: 69.5 %

Procedure:
4-Bromo-6-(trifluoromethyl)-1H-indazole (40 mg, 0.151 mmol), (3-sulfamoylphenyl)boronic acid (45.5 mg, 0.226 mmol), PdCl2(dppf) (11.04 mg, 0.015 mmol), sodium bicarbonate (323 μL, 0.604 mmol), and dioxane were mixed in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140° C. for 20 minutes in a microwave reactor. The reaction mixture was subsequently filtered and the product was purified by preparative HPLC, eluting with a gradient of 35-70% ACN in H2O (containing 10 mM NH4HCO3). The pure fractions were lyophilized to give the title compound as a white solid (35.8 mg, 69.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (s, 2H), 7.53 (s, 1H), 7.75-7.80 (m, 1H), 7.92-7.94 (m, 1H), 8.02 (s, 1H), 8.06 (dt, J=8.02, 1.29 Hz, 1H), 8.21 (t, J=1.64 Hz, 1H), 8.40 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C14H10F3N3O2S, 342.0. found 342.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCN
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc2c(N)nc3c(c2c1CCCCN)CCCC3
Reaction time: 48 h

Procedure:
Platinum (IV) oxide (4 g) was added to a solution of 1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (approximately 24 mmol, prepared as described in Part A of Examples 349-453) in trifluoroacetic acid (80 mL), and the mixture was shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for two days and subsequently filtered through a layer of CELITE filter agent. The filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. Water (10 mL) was added, and the resulting solution was adjusted to pH 14 with the addition of 50% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane, and the extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-(4-aminobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:24])[CH2:22][SH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:20][C:21](=[O:24])[CH2:22][S:23][CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)NC(CI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCC(NC(=O)OC(C)(C)C)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A mixture of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester (3.88 g, 10.6 mmol), mercapto-acetic acid methyl ester (1.24 g, 11.7 mmol) and potassium carbonate (12.21 g, 18 mmol) in acetone (100 mL) was heated to reflux with stirring for 90 minutes. The mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from hexanes to give 3.34 g of [2-tert-Butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester, MP=61-62° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[N:11]=1)[CH2:6][C:7]([OH:9])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C=O)C>[C:1]([CH2:3][CH2:4][N:5]([C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[N:11]=1)[CH2:6][C:7]([N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:9])#[N:2]
Reactant: CCNCC
Reactant: Cc1cc(N(CCC#N)CC(=O)O)nc(-n2ccnc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN(CCC#N)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid (1.53 g, 5.3 mmol) slurried in DMF (25 mL) was added carbonyldiimidazole (0.87 g, 5.4 mmol). After stirring for 2 hours, diethylamine (1.0 mL, 9.7 mmol) (a compound of formula Y4)) was added. After stirring for 18 hours, the reaction was partitioned with ethyl acetate and water. The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo to give 0.91 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6methyl-4-pyrimidinyl]amino)-N,N-diethylacetamide (a compound of formula (Yc3)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:28])([F:27])[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]3)=[CH:4][CH:3]=1.COCCOC.C(Cl)Cl>Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: COCCOc1cnc2ccc(C(F)(F)C(=O)NNc3ccc(Cl)nn3)cc2c1
Agent: Cl
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Temperature: 130 °C
Yield: 56.2 %

Procedure:
A sealable microwave vial was charged with N′-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide (46.98 mg, 111 μmol), 1,2-dimethoxyethane (1.5 mL), and 1 drop of conc. HCl. The vial was sealed and heated at 130° C. for 40 min. The solution was concentrated and purified by MPLC (Teledine Isco combiFlash Companion). The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH to afford 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline (25.3 mg, 56.2% yield) as a colorless solid. LRMS (ESI) m/z calcd for C18H15ClF2N5O2 (M+H) 406.1. found 406.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1.Cl[C:14]1C=C(CC)C=CN=1>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1)[CH3:14]
Reactant: CCCCCc1cc(C)ccn1
Reactant: CCc1ccnc(Cl)c1
Product: CCCCCc1cc(CC)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using 2-chloro-4-ethyl pyridine instead of 2-bromo-4-methyl pyridine. The product was obtained with similar yield and purified in the same way.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])[CH2:11][CH2:10]1)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH2:14][CH2:13]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirred solution of 9.0 g (0.020 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinepentanoic acid ethyl ester in 300 ml of 95% ethanol was added a solution of 21.0 g (0.250 mole) of sodium bicarbonate in 250 ml of water, and the mixture was heated at reflux for 6 h under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl ether and water (300 ml each). The layers were separated, and the aqueous layer was further extracted with three 300 ml portions of ethyl ether. The aqueous layer pH was adjusted to 6 with glacial acetic acid, whereupon a soid precipitate began to form. After standing for 16 h the crystals were collected by filtration, washed with water and recrystallized from benzene to yield 4.2 g (52%) of the title compound as a white solid, mp 105°-107° C.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)CCC>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:28][CH2:27][CH2:25][OH:26])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Agent: Cl
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cc1OC
Temperature: 110 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (63 mg; 0.172 mmol) and ethanolamine (32 μL; 0.53 mmol) in n-butanol (2 mL) was heated at 110° C. for 24 h then concd in vacuo. The material was partitioned between DCM (5 mL) and satd NaHCO3 (3 mL). The organic layer was dried (MgSO4), filtered through silica and washed with 100:10:1 CHCl3:MeOH:concd NH4OH, concd then purified by pTLC (EM-13793; 100:10:1 CHCl3:MeOH:concd NH4OH) yielding a pale yellow glass (52 mg; 85%). 1H NMR (CDCl3) δ 7.44-7.34 (m, 2H), 6.88 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.75-6.67 (m, 3H), 5.42 (t(br), 1H), 3.91 (s, 3H), 3.91 (m, 2H), 3.79 (s, 3H), 3.68 (m, 2H), 3.50 (s, 3H); LC-MS (ESI+; 355 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]O)[CH:21]=2)[CH:19]=1)=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:30]=[N:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:16]=3[N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(hydroxymethyl) phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.45 g, 0.1.011 mmol) in a DCM (10 mL), PPh3 (0.477 g, 1.81 mmol) was added at 0° C. & then stirred for 5 min. After that CBr4 (0.636 g, 1.92 mmol) was added and stirred at room temperature for 1 hr. After completion of reaction, solid was filtered & washed with small amount of DCM to afford 0.30 g of pure desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[CH2:10][CH2:9][NH:8][C:7]2=[O:11])=[N:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:45])[C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=3[Cl:44])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(#N)C>[Cl:44][C:35]1[CH:36]=[CH:37][C:38]([C:40]([F:41])([F:42])[F:43])=[CH:39][C:34]=1[C:33]([NH:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:25][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[CH2:10][CH2:9][NH:8][C:7]3=[O:11])=[N:2]2)[CH2:27][CH2:28]1)=[O:45]
Reactant: O=C1NCCN1c1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(N[C@H]1CC[C@H](Cn2ccc(N3CCNC3=O)n2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(1H-pyrazol-3-yl)imidazolidin-2-one (410 mg, 2.69 mmol) is placed in a microwave vial with acetonitrile (12 mL). NaH (60%, 108 mg, 2.69 mmol) is added and the reaction mixture is stirred at RT for 30 minutes. Trans-(4-(2-chloro-5-(trifluoromethyl)benzamido)cyclohexyl)methyl 4-methylbenzenesulfonate (1.20 g (0.20 mmol) is added and the mixture is heated using microwave radiation at 120° C. for 30 minutes. The mixture is partitioned between DCM and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The product is purified by crystallization (EtOAc with a small amount of MeOH) to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][S:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>ClCCl.C1(C)C=CC=CC=1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:22][S:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCSSc1ccccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)CCOCCOCCOCCOCCSSc1ccccn1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 140 mg of 15-(2-pyridyldithio)-4,7,10,13-tetraoxapentadecanoic acid tert-butyl ester (13a) in 5 ml of dichloromethane was added 1.0 ml of TFA and 250 μl of Et3SiH. After stirring for 2 hrs, the mixture was diluted with 5 ml of toluene. The mixture was evaporated and then co-evaporated three times with 5 ml of toluene and dried under vacuum to yield of 122 mg (99% yield) of the title compound 14a (FIG. 7). 1H NMR (CDCl3) 13.331 (s, OH), 8.770 (d, 1H, J=5.4 Hz), 8.299 (t, 1H, J=7.7+7.7 Hz), 8.130 (d, 1H, J=8.2 Hz), 7.677 (t, 1H J=6.3+6.4 Hz), 3.703˜3.556 (m, 16H), 3.109 (t, 2H, J=6.4+6.4 Hz), 2.538 (t, 2H, J=6.1+6.1 Hz); 13C NMR 175.900, 157.402, 144.807, 129.114, 124.746, 123.635, 70.452, 70.327, 70.206, 70.184, 69.881, 69.862, 67.229, 66.407, 39.320, 34.866; MS 392.73 (M+H)+, 390.76 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c(Cc2cccc3ccccc23)c2ccccc21
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (50 mg, from Exp. 64.2.) in dimethylformamide (1.5 ml) was added NaH (1.3 eq.), the mixture was stirred at 22° C. for 30 min. and cooled to 0° C. Ethylbromo acetate (33 mg) was added, the mixture was stirred for 2 h and partitioned between aqueous NH4Cl and AcOEt. The organic layer was dried, evaporated and the residue was chromatographed on silica (n-heptane/AcOEt, 10:1) to give 1-ethoxycarbonylmethyl-3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 358.2 ([M−H]−).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:21]([CH:23]1[CH2:25][CH2:24]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:21][CH:23]1[CH2:25][CH2:24]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C1CC1)N1CCCCCC1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CC2CCCCCN2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
Dissolve in 9.0 g of the title compound of Example 28 in 80 ml of tetrahydrofuran. Add the resulting solution (drop by drop over a period of 10 minutes while stirring at 0°) to a suspension of 1.30 g of lithium aluminum hydride (=lithium hydridoaluminate) in 30 ml of tetrahydrofuran. Then boil the prepared admixture for 1.5 hours under reflux before adding a further 2.0 g of lithium aluminum hydride thereto and boiling for a further 3.5 hours under reflux. Cool the refluxed product to ambient temperature. Carefully add 300 ml of water to the cooled material and extract it 3 times with 50 ml of diethyl ether (each time). Wash the combined ether solutions with saturated common salt solution. Dry the washed solutions over sodium sulfate. Evaporate off the solvent in vacuo. Distil the residue to obtain 5.89 g of the title compound with a BP at 115° at 0.01 mm of Hg.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])C.[N:14](C(Cl)=O)([CH3:16])[CH3:15]>>[C:6]([NH:5][NH:4][C:1](=[O:3])[N:14]([CH3:16])[CH3:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)NNC(=O)c1ccccc1
Product: CN(C)C(=O)NNC(=O)c1ccccc1

Procedure:
Synthesis and isolation were same as 1-acetyl-2-benzoylhydrazine, using 1.5 g (11.2 mmol) of benzoylhydrazide, 1.2 g (11.2 mmol) of (CH3)2NCOCl and 1.11 g of TEA. Yield was 0.9 g (39%). 1H NMR (200 MHz, d6-DMSO) δ 2.90 (s, 6H), 7.50 (m, 3H), 7.90 (d, 3H), 8.45 (s, 1H), 10.05 (s, 1H); MS (EI, m/e, relative intensity %) calcd for C10H13N3O2 207, found 207 (M, 13.2); mp 199-201° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) in dichloromethane (5.5 mL) was added trifluoroacetic acid (800 mg, 541 μL, 7.02 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (5 mL), methanol (2.5 mL) and ammonium hydroxide (0.7 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 269 μmol, 77%) as an off white solid.