Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:14](Br)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Br)C1C=CC=CC=1>>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: BrCc1ccccc1
Product: COC(=O)c1ccc2ccn(CCc3ccccc3)c2c1
Yield: 19.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.00 g of methyl indole-6-carboxylate and 2.54 g of phenethyl bromide instead of the indole-4-carbaldehyde and benzyl bromide used in Example 1 to give 0.61 g of methyl 1-phenethylindole-6-carboxylate as a yellow oily substance. The yield thereof was found to be 19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])N.C(C1C=C(C=C(C(O)=O)C=1)[NH2:20])(O)=O>>[CH3:1][O:2][CH:3]1[CH:9]([O:10][CH3:11])[CH:8]([O:12][CH3:13])[CH2:7][CH2:5][CH:4]1[NH2:20]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Product: COC1CCC(N)C(OC)C1OC

Procedure:
3,4,5-trimethoxyaniline was hydrogenated via the procedure given for 3,5-dicarboxy-aniline to provide 2,3,4-trimethoxycyclohexylamine which was coupled to the C-terminal valine in the standard way.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2c(OC)nc(Oc3ccc(F)c(F)c3)nc2-c2ccc(Cl)cc2Cl)c1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (53 mg, 0.1 mmol) as described in Reference Example 17 and 3-methoxybenzeneboronic acid (Lancaster, 16 mg, 0.1 mmol). HPLC Rt=4.63 min. 1H-NMR 500 MHz (CDCl3): 3.77 (s, 3H), 4.12 (s, 3H), 6.51 (m, 1H), 6.72 (m, 2H), 6.75 (m, 1H), 6.90 (dd, J=8 Hz, J=2 Hz, 1H), 7.07 (q, J=9 Hz, 1H), 7.25 (t, J=4 Hz, 1H), 7.43 (d, J=2 Hz, 2H), 7.49 (d, J=2 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH:15]2[CH2:18][N:17]([CH3:19])[CH2:16]2)[C:13]#[N:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:26]>CC(CC(C)C)=O>[ClH:26].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH:15]2[CH2:18][N:17]([CH3:19])[CH2:16]2)[C:13]([NH2:14])=[O:2])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: CN1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CC(=O)CC(C)C
Product: CN1CC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C

Procedure:
To 60 ml. of concentrated sulfuric acid preheated to 60° C. was added 21.7 g. (0.082 mole) of α,α-diphenyl-α-(1-methyl-3-azetidinyl)acetonitrile at a rate so as to maintain a temperature of 60°-70° C. The solution obtained was heated to 70° C. for 18 hrs. and extracted with chloroform. The chloroform extract was dried over sodium sulfate and concentrated and the residue crystallized from ethyl acetate-isopropyl alcohol to give 13.8 g. of the free base (60%) melting at 171°-174° C. The base was treated with hydrogen chloride in isobutyl methyl ketone and the salt recrystallized from isopropyl alcohol to give 9 g. of product melting at 182°-185° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]1([CH2:29][O:30][C:31]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:28][CH2:27]1>CCCCCCC.CCOC(C)=O>[CH:26]1([CH2:29][O:30][C:31]2[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:28]1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: CC1(C)OB(c2cccnc2OCC2CC2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC1CC1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(cyclopropylmethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN 848243-26-5) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (63%). MS (ESI): m/z=498.146 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:24]C)=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[CH:7]([CH2:8][C:9]4[C:18]([Cl:19])=[CH:17][C:16]([O:20]C)=[C:15]([OH:22])[C:10]=4[CH2:11]3)[C:6]=2[CH:23]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[CH:7]([CH2:8][C:9]4[C:18]([Cl:19])=[CH:17][C:16]([OH:20])=[C:15]([OH:22])[C:10]=4[CH2:11]3)[C:6]=2[CH:23]=1
Reactant: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(O)c3CN1CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc2c(cc1O)C1Cc3c(Cl)cc(O)c(O)c3CN1CC2
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A product obtained in Example 1 (0.3 g, 0.66 mmol) was dissolved in CH2Cl2 (20 ml), adding a solution of BBr3 (0.32 ml) in CH2Cl2 (5 ml) under ice-salt bath. The mixture was stirred for 1 hours at this temperature, then stirred at room temperature overnight. The reactant solution produced yellow precipitate. The mixture was poured into water and stirred for 30 minute. After filtering, the solid was dissolved with methanol. Then the mixture was filtered. The filtrate was evaporated under reduced pressure, followed by recrystallizing with methanol to give yellow solid (0.15 g, 67.7%). mp 295˜296° C. 1HNMR (DMSO-d6) δ: 2.65˜2.86 (3H, m, CH2), 3.05˜3.63 (5H, m, CH2 or N—CH), 4.29 (1H, d, CH2), 6.59 (1H, s, ArH), 6.81 (1H, s, ArH), 6.92 (1H, s, ArH). MS (EI) m/z: 333 (M+), 299, 164 (base), 107, 80.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].O>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: ClCc1ccccn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccn1
Yield: 57.7 %

Procedure:
2-(Chloromethyl)pyridine hydrochloride (303 mg) was suspended in N,N-dimethylformamide (3 ml), potassium carbonate (256 mg) was added thereto, and the mixture was stirred. Then, to the suspension was added a solution of (3,3,3-trifluoropropyl)malononitrile (300 mg) in N,N-dimethylformamide (3 ml), and further thereto was added potassium carbonate (256 mg), followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 270 mg of 2-((2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1.O[N:29]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:29])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Temperature: 100 °C
Yield: 64 %

Procedure:
5-bromo-3-(1,1-dioxido-2-phenyltetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylic acid (0.9 g, 2.007 mmol) was put in a flask and dissolved in N,N-Dimethylformamide (DMF) (2 mL). HOBt (1-hydroxybenzotriazole) (0.271 g, 2.007 mmol) and EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.078 g, 5.62 mmol) were added. The mixture was stirred and 0.5N NH3 in dioxane was added (12.04 mL, 6.02 mmol). The reaction mixture was heated under microwave at 100° C. for 20 minutes. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×25 mL). Organic layers were combined and washed with a saturated aqueous solution of sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The mixture was dissolved in the minimum amount of DCM and precipitated in hexane, giving 0.575 g of the title compound as a pale brown powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH2:23]([N:25]([CH2:44][CH3:45])[C:26](=[O:43])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=3[CH3:33])[C:26]([N:25]([CH2:44][CH3:45])[CH2:23][CH3:24])=[O:43])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CCN(CC)C(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.720 g, 2.1 mmol), N,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above (1.09 g, 3.15 mmol), and K2CO3 (0.868 g, 6.3 mmol), were taken up in dioxane (42 mL) and water (8.5 mL). The mixture was degassed with argon for 30 min and tetrakis-(triphenylphosphine)palladium(0) (0.183 g, 0.15 mmol) was added. The mixture was then heated under argon at 950 C for 18 h. The solvents were pumped off and after aqueous workup, the crude material was flashed on silica gel (150 g) eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 127-129° C. LC-MS m/z 498 (M+H)+, 2.11 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH:19]=[CH2:18]
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Reactant: C=CCBr
Product: C=CCN1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and allylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV)) 305 (M+, 7), 96 (57), 69 (bp), 68 (48), 56 (69).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([Sn:20]([CH3:23])([CH3:22])[CH3:21])[CH:4]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([Sn:20]([CH3:21])([CH3:23])[CH3:22])[CH:4]=1
Reactant: COc1cc([Sn](C)(C)C)c(C=O)cc1OCOCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([Sn](C)(C)C)c(CO)cc1OCOCC[Si](C)(C)C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
4-Methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde (2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0° C. Sodium borohydride (400 mg, 10.6 mmol) was added, and the reaction stirred for 1 h. The solution was diluted with H2O (60 mL), and extracted with EtOAc (2×50 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo to give 2.16 g (91%) of [4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.18 (t, 1H, J=6.9 Hz), 7.03 (t, 1H, J=9.3 Hz), 5.27 (s, 2H), 4.58-4.63 (m, 2H), 3.89 (s, 3H), 3.80 (t, 2H, J=8.4 Hz), 1.53 (t, 1H, J=6.0 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.31 (t, 9H, J=27.3 Hz), 0.01 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[CH3:30][S:31]([C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].Cl>>[CH3:30][S:31]([C:34]1[CH:35]=[C:36]([NH:40][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:29])[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:33]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 573.2 [(M+H)+]; mp 215° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 22.7, 29.3, 31.9, 43.1, 62.5, 104.7 (t, J 25.8), 112.0 (dd, J 22.9 and 3.5), 127.3, 129.6, 131.5 (d, J 8.8), 131.5 (d, J 9.8), 139.1, 139.4, 159.8 (dd, J 252.0, 11.7) and 163.0 (dd, J 252.0, 11.7).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:11]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Yield: 53 %

Procedure:
A solution of 11.0 g of 6-tert-butyl-1-indanone, 12.5 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 41 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 7.35 g (53%) of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone was obtained as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][CH2:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:22]([S:29][CH2:30][C@H:31]([NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:33](=[O:34])[NH:35][CH2:36][CH2:37][CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCNC(=O)[C@@H](N)CSCc1ccccc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@H](CSCc1ccccc1)NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), S-benzyl-N-propyl-L-cysteinamide (0.27 g), 1H-1,2,3-benzotriazol-1-ol (0.22 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (285 mg, yield 49%) as colorless crystals. melting point 124-125° C.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11](O)=[O:12])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[N:48]=[C:47]1[C:55]1[C:56]([NH2:67])=[N:57][CH:58]=[C:59]([C:61]2[CH2:62][CH2:63][NH:64][CH2:65][CH:66]=2)[N:60]=1>CS(C)=O>[NH2:67][C:56]1[N:57]=[CH:58][C:59]([C:61]2[CH2:62][CH2:63][N:64]([C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH3:6])[CH2:65][CH:66]=2)=[N:60][C:55]=1[C:47]1[NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[N:46]=1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNCCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.6 %

Procedure:
To a solution of 3-[tert-butoxycarbonyl(methyl)amino]propanoic acid (14 mg, 0.07 mmol) in DMSO (445 μL) was added HATU (26 mg, 0.07 mmol) followed by the addition of triethylamine (28 mg, 38 μL, 0.27 mmol) and 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (20 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (Na2SO4), filtered and concentrated. To the crude material was added 1:1 DCM:TFA (3 ml) and it was stirred for 1 h. The solvents were evaporated under reduced pressure and the crude material obtained was dissolved in DMSO and purified by reverse phase chromatography using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 1-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(methylamino)propan-1-one (2 mg, 7%). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=15.9 Hz, 1H), 7.81 (dd, J=6.1, 3.1 Hz, 2H), 7.52 (dd, J=6.0, 3.1 Hz, 2H), 6.88 (d, J=20.4 Hz, 1H), 4.33 (dd, J=13.5, 2.6 Hz, 2H), 3.85 (dt, J=39.3, 5.6 Hz, 2H), 2.95 (dt, J=24.1, 6.0 Hz, 2H), 2.82 (s, 1H), 2.75 (s, 4H). LC/MS m/z 378.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32].CO>CN(C=O)C>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2nnc(-c3cnccn3)n2CCN1Cc1cccc(Cl)c1Cl
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a slurry of Intermediate 1 (60 mg, 0.18 mmol) and cesium carbonate (237 mg, 0.73 mmol) in DMF (1.4 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (65 mg, 0.27 mmol). After 5 h, the reaction was quenched with sat aq NH4Cl, poured into brine, and extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give a brown sludge. Trituration with MeOH provided the desired product as a beige powder (60 mg, 88%). MS (ESI): mass calcd. for C16H12Cl2N6O, 374.0; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.77 (s, 2H), 7.57 (dd, J=7.9, 1.2 Hz, 1H), 7.49-7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 4.86-4.75 (m, 4H), 3.90-3.81 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:3]#[CH:4].Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[C:3]#[C:4][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: C#CC(O)c1ccc(O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(O)cc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne (120 mg, 0.84 mmol) (from Example 17 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-hydroxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 62 mg, 47%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[CH2:12][CH2:11][CH:10]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:9][CH2:8]1
Reactant: O=C1CCOCC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (3.7 g) and tetrahydro-4H-pyran-4-one (5.2 g) in acetic acid was added sodium cyanoborohydride (14 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.92 g, 10%).