Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([I:29])=[N:8][N:9]([CH2:16][CH:17]([NH:21][C:22](OC(C)(C)C)=[O:23])[CH:18]2[CH2:20][CH2:19]2)[C:10]=1C(OCC)=O)=[O:5])[CH3:2].Cl>O1CCOCC1>[CH:18]1([CH:17]2[CH2:16][N:9]3[N:8]=[C:7]([I:29])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]3[C:22](=[O:23])[NH:21]2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1c(I)nn(CC(NC(=O)OC(C)(C)C)C2CC2)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)NC(C1CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a stirred solution of Intermediate 348B (8.0 g, 15.34 mmol) in 1,4-dioxane (10.0 mL) was added 4 M HCl in dioxane (40.0 mL, 160 mmol) and the resulting solution stirred at RT for 2 h. The reaction mixture was concentrated and diluted with EtOAc (50 mL). The organic layer was washed successively with water, a saturated aq. solution of NaHCO3, and brine, then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue obtained was heated in a ROTAVAPOR® at 60° C. for 5 h. The solid product was triturated with diethyl ether to afford Intermediate 348C as an off-white solid (1.6 g, 28%). MS(ES): m/z=376 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.67 (d, J=2.27 Hz, 1H), 4.47 (dd, J=13.22, 4.53 Hz, 1H), 4.17-4.33 (m, 3H), 3.15 (d, J=9.07 Hz, 1H), 1.28 (s, 3H), 0.90 (d, J=8.69 Hz, 1H), 0.40-0.54 (m, 2H), 0.20-0.37 (m, 2H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH-].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O.CO>[C:1]([O-:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C([O-])C(=O)O

Procedure:
Oxalic acid in an amount of 21.56 g (0.239 mol) was dissolved in acetone, making a total of 100 g. The resultant solution was mixed with 100 g of 40% by weight solution of benzyltrimethylammonium hydroxide (0.261 mol) in methanol (produced by Tokyo Kasei Kogyo Co., Ltd.), and then 1500 g of acetone was added to the resultant mixture to form white precipitate. Subsequently, the precipitate was collected by means of suction filtration method, dispersed in 500 g of acetone and filtered to collect cake. The resultant cake was subjected to drying treatment under vacuum at 80° C. for 24 hours to form 46.80 g (0.208 mol) of mono(benzyltrimethylammonium) oxalate at a yield of 87.0% based on the fed oxalic acid. The resultant mono(benzyltrimethylammonium) oxalate, which had a melting point of about 130° C. in a stream of nitrogen, was thermally decomposed in a stream of nitrogen at about 230° C. with a latent heat of fusion of about 123 J/g.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][N+:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)=[CH:7][CH:6]=1.[BH4-].[Na+].CCOC(C)=O>CO>[F:2][CH2:3][CH2:4][N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(-c2cc[n+](CCF)cc2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C2=CCN(CCF)CC2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To 1-(2-fluoroethyl)-4-[3-(methyloxy)-4-nitrophenyl]pyridinium bromide (2.0 g, 5.6 mmol) in MeOH (10 mL) cooled in an ice bath was added NaBH4 (1.1 g, 28 mmol) at such a rate to control the foaming which occurred. The mixture was stirred for 2 h then rotovaped down. EtOAc (200 mL) was added, and the solution was washed with saturated NaHCO3 solution and H2O. The solution was dried (MgSO4), filtered, rotovaped and purified by silica gel chromatography. The desired fractions were combined and rotovaped to give the title compound of step B (0.90 g, 3.2 mmol, 57%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 1H), 7.05-7.00 (m, 2H), 6.22-6.18 (m, 1H), 4.73 (dd, J=5.1, 4.8 Hz, 1H), 4.61 (dd, J=5.1, 4.8 Hz, 1H), 3.97 (s, 3H), 3.36-3.31 (m, 2H), 2.94-2.82 (m, 4H), 2.65-2.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[I:26]I>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:26])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ncnc32)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [5.4 g, Reference Example 3], in tetrahydrofuran (96 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (12.1 mL, 1.6M) under inert atmosphere. The solution was stirred at −78° C. for 3 hours and iodine (8.9 g) was added. The reaction mixture was stirred at −78° C. for 2 hours, and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (1.52 g) as an amorphous solid. MS: 434 [MH]+. LCMS (Method B) RT=4.26 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:9]([CH2:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1)=[N+:10]=[N-:11]
Reactant: Cc1nnc(CCl)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(CN=[N+]=[N-])o1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
A solution of 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (R. Rufenacht, Helv. Chim. Acta, 55, 1979, 1972) (2.00 g, 15.09 mmol) in N,N-dimethylformamide (75 ml) was treated at 22° C. with sodium azide (3.0 g, 46.1 mmol) and the resulting mixture was stirred for 18 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by chromatography of the residue on silica gel (elution toluene-ethyl acetate 0-10%) gave 1.78 g (84% yield) of the title azide as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.60 (3H, s, CH3), 4.55 (2H, s, CH2). MS (ESI+) m/e 140 [M+H+].
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: N#Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 84%), MS (ISP) m/z=324.4 [(M+H)+], mp 289.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C@H:2]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:15][C:12]([F:13])([F:14])[C:11]([NH:10][C@@H:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:6][CH:5]=1)=[O:16]
Reactant: C[C@@H](Cc1ccccc1)NC(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](Cc1ccc(S(=O)(=O)Cl)cc1)NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 2.0 g (8.64 mmol) of (S)-N-(1-methyl-2-phenylethyl)trifluoroacetamide (15) in 200 mL of chloroform was added 24 mL of chlorosulfonic acid dropwise at 0° C. The mixture was stirred at 0° C. for 4 hours. The reaction mixture was poured into 100 mL of ice water and extracted with 3×200 mL of chloroform. The organic layers were combined, dried over anhydrous sodium sulphate and evaporated to yield 2.58 g (7.82 mmol, 90%) of (S)-4-[2-[(trifluoroacetyl) amino]propyl]-benzenesulfonyl chloride (16) as a white solid. NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C)CC1)C3
Yield: 35.4 %

Procedure:
A mixture of Example 64 (100 mg; 0.21 mmol; 1 eq.), paraformaldehyde (56 mg; 0.62 mmol; 3 eq.) and sodium triacetoxyborohydride (88 mg; 0.42 mmol; 2 eq.) in DCE (7 mL) was stirred at reflux for 16 hours. Paraformaldehyde (56 mg; 0.62 mmol; 3 eq.) and sodium triacetoxyborohydride (88 mg; 0.42 mmol; 2 eq.) were added and the reaction mixture was stirred at reflux for one hour. The mixture was partitioned between EA and 1M NaOH and the aqueous layer extracted with EA. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (2% to 5% MeOH in DCM) followed by recrystallization from ACN afforded the title compound (34 mg, 35%) as a white powder. 1H NMR (DMSO-d6) δ 7.44-7.25 (m, 1H), 7.13 (d, J=11.4 Hz, 1H), 6.86 (td, J=8.3, 2.0 Hz, 1H), 4.92-4.69 (m, 2H), 4.69-4.37 (m, 3H), 2.93-2.70 (m, 3H), 2.61 (s, 1.5H), 2.55 (s, 1.5H), 2.42-2.23 (m, 2H), 2.23 2.04 (m, 2H), 2.04-1.93 (m, 3H), 1.91-1.73 (m, 2H), 1.64-1.47 (m, 2H). HPLC (max plot) 97.4%, Rt 2.81 min. UPLC/MS: (MS+) 458.5 ([M+H]+).
Reaction SMILES: C1(CN(CC2CC2)[C:6]2[N:11]=[C:10]3[N:12]([CH3:16])[C:13]([CH3:15])=[N:14][C:9]3=C[C:7]=2C=O)CC1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN.C(O)(=[O:41])C.[BH3-]C#N.[Na+]>CO>[CH3:15][C:13]1[N:12]([CH3:16])[C:10]([NH:11][C:6](=[O:41])[CH3:7])=[CH:9][N:14]=1
Reactant: Cc1nc2cc(C=O)c(N(CC3CC3)CC3CC3)nc2n1C
Reactant: CC(=O)O
Agent: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cnc(C)n1C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde (0.220 g, 0.73 mmol.) and 3,5-bis-trifluoromethyl-benzylamine (215 mg, 0.87 mmol) in methanol (8 mL) was added acetic acid (0.042 mL, 0.073 mol) at 0° C. and the resulting reaction mixture was stirred for 15 min at the same temperature. NaCNBH3 (0.069 g, 0.011 mmol.) was added and the mixture was stirred at room temperature for 45 min. Methanol was removed under reduced pressure and the crude was extracted with ethyl acetate (250 mL) and washed with water (250 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 gof colorless gummy compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:18]1[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.2 g (30.0 mmol) of potassium carbonate and 3.0 mL (30.0 mmol) of 4-hydroxypiperidine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 4.65 g (83%) of the desired product as a tan oil. MS (ion spray) 188.0 (M+).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:31]([F:34])([F:33])[F:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N+:28]([O-])=O)[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Zn]>[NH2:28][CH:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[C:13]=2[C:31]([F:33])([F:34])[F:32])[CH:18]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(CCC(=O)O)[N+](=O)[O-])ccc3c2C(F)(F)F)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(N)CCC(=O)O)ccc3c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Zinc (0.194 g, 2.96 mmol) was added to a solution of 4-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-nitro-butyric acid (0.102 g, 0.212 mmol) in acetic acid (3.00 mL, 52.8 mmol). The mixture was stirred for 2 hours at room temperature. HPLC analysis showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The resulting crude product was dissolved in DMSO (4 mL) and purified by HPLC. The product was dried for 2 days under vacuum to give 28 mg of the title compound as a white solid (26% yield). MS: m/z=435.66 [M−16]+. 1H NMR (MeOD, 400 MHz): δ=8.24-8.30 (m, 1H), 8.09-8.14 (m, 1H), 7.92-7.96 (m, 1H), 7.56-7.65 (m, 2H), 4.45-4.57 (m, 2H), 2.65-2.69 (m, 2H), 2.26-2.46 (m, 4H), 2.18-2.26 (m, 2H), 1.87-1.97 (m, 2H), 1.45-1.58 (m, 2H), 1.18-1.31 (m, 2H), 1.06-1.17 (m, 1H), 0.92 (s, 9H)
Reaction SMILES: [CH:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[P]>C(O)(=O)C>[CH:1]1([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1ccncc1)(c1ccc(F)cc1)C1CCCCC1
Agent: I
Agent: [P]
Solvent: CC(=O)O
Product: Fc1ccc(C(c2ccncc2)C2CCCCC2)cc1
Yield: 19 %

Procedure:
A mixture of α-cyclohexyl-α-(4-fluorophenyl)-4-pyridinemethanol (16.54 g, 0.058 mole), 57% hydrogen iodide (250 ml), glacial acetic acid (250 ml), and phosphorus (50.0 g) was heated overnight at reflux. The reaction mixture was cooled and filtered through Celite®. The volume of the filtrate was concentrated to 100 ml. Ice/50% sodium hydroxide was added, and the aqueous phase was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and water. The organic layer was dried over sodium sulfate and filtered, and solvent removed to give a green oil. A 4 g portion of this oil was subjected to flash chromatography on silica gel using 20% ethyl acetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil. This oil was dried in vacuo overnight at 80° C. The oil crystallized to give 2.95 g (19% yield) of white, crystalline solid, mp 78°-81° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[C:27](=[O:28])[NH:26][C:25]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C:23]=3[N:24]=2)=[CH:14][CH:13]=1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:35]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:20]=[CH:21][C:22]4[C:27](=[O:28])[NH:26][C:25]5([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[C:23]=4[N:24]=3)=[CH:14][CH:13]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1
Reactant: C1CNCCN1
Reactant: O=C1NC2(CCCCCC2)c2nc(Nc3ccc(Br)cc3)ncc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC2(CCCCCC2)c2nc(Nc3ccc(N4CCNCC4)cc3)ncc21
Temperature: 100 °C

Procedure:
Lithium bis(trimethylsilyl)amide, (1.0M solution in tetrahydrofuran, 1.68 ml, 1.68 mmol) under an atmosphere of N2 was added to a solution of 2′-((4-bromophenyl)amino)spiro[cycloheptane-1,7′-pyrrolo[3,4-d]pyrimidin]-5′(6′H)-one (136) (0.217 g, 0.560 mmol), and piperazine (0.145 g, 1.68 mmol) in anhydrous toluene (3 ml). After degassing the solution with nitrogen, S-Phos (0.092 g, 0.224 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (0.051 g, 0.056 mmol) were added and the reaction was heated at 100° C. for 2 hrs. Additional lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (1.68 ml, 1.68 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.051 g, 0.056 mmol), and S-Phos were added (0.092 g, 0.224 mmol) and the reaction was heated at 100° C. for another 1 hr before it was cooled to 20° C. The reaction was quenched with methanol and concentrated under vacuum. The residue was triturated with DCM and solids removed by filtration. The filtrate was concentrated under vacuum and purified by preparative HPLC eluting with a gradient of 20% MeCN-60% MeCN/H2O/0.1% TFA. The fractions containing the product were combined and concentrated under vacuum. Trituration with methanol gave 2′4((4-(1-piperazinyl)phenyl)amino)spiro[cycloheptane-1,7′-pyrrolo[3,4-d]pyrimidin]-5′(6′H)-one (131) as a white solid (26 mg, crude). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.02 (1H, s), 8.75 (1H, s), 8.73 (2H, br. s.), 8.62 (1H, s), 7.68 (2H, d, J=8.5 Hz), 6.99 (2H, d, J=9.2 Hz), 3.28-3.32 (4H, m), 3.21-3.28 (4H, m), 1.92-2.02 (2H, m), 1.77-1.86 (2H, m), 1.55-1.77 (8H, m); LCMS-ESI (POS), M/Z, M+1: Found 393.2.
Reaction SMILES: O.O.[C:3]([OH:34])(=[O:33])[CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[CH:32]=[CH:31][C:16]([NH:17][CH2:18][C:19]2[N:30]=[C:29]3[C:22]([N:23]=[C:24]([NH:26][C:27]3=[O:28])[NH2:25])=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=[O:8].[OH-].[Na+].[BH4-].[Na+].Cl.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.SC(O)C>O>[C:3]([OH:34])(=[O:33])[CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:17][CH2:18][CH:19]2[NH:30][C:29]3[C:27](=[O:28])[NH:26][C:24]([NH2:25])=[N:23][C:22]=3[NH:21][CH2:20]2)=[CH:31][CH:32]=1)=[O:12])[C:7]([OH:9])=[O:8]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: CC(O)S
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a suspension of folic acid dihydrate (47.8 g, 100 mmol) in deaerated H2O (1,000 ml), which was cooled in an ice bath, was added slowly with stirring 50% NaOH (10.5 ml). The resulting dark yellow solution (pH 8.0, meter) was treated over a 10-min period with a solution of NaBH4 (58 g) in H2O (150 ml). The solution was stirred for an additional 30 min, the pH increasing during this period from 8.4 to 8.8. Excess NaBH4 was decomposed by the addition of 6 N HCl (caution, vigorous effervescence) until the pH of the solution was 6.8. Solid ascorbic acid (5 g) was added and stirring continued until complete dissolution occurred. The resulting solution was adjusted to pH 3.7 with 6 N HCl (total volume, 165 ml). The cream-colored precipitate was collected by filtration under N2, washed with ice cold HCl (pH 3.5, 200 ml) containing ascorbic acid (2 g) and dried to constant weight in vacuo over P2O5 at room temperature: yield, 60.0 g (96%). Solutions for the uv spectra determinations were obtained by dissolution of tetrahydrofolic acid (5.5 mg) by the successive addition of mercaptoethanol (2.5 ml) and water (22.5 ml) and dilution of the resulting stock solution with the appropriate solvent (5→50 ml). λmax, nm (ε×10-3): 0.1 N HCl-270 (23.5), 292 (20.8); pH 7-297 (25.7); 0.1 N NaOH-297 (25.9). TLC [DEAE cellulose; 0.005 M KH2PO4 +0.5 M NaCl+0.2 M mercaptoethanol (pH 7)]-Rf ~0.44 (elongated).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([N:20]([CH2:22][CH2:23][OH:24])[CH3:21])=[C:18]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:17]([C:32]#[N:33])=[N:16]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[C:19]([N:20]([CH3:21])[CH2:22][CH2:23][O:24][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:18]([S:25]([C:28]([F:31])([F:29])[F:30])(=[O:26])=[O:27])[C:17]([C:32]#[N:33])=[N:16]1
Reactant: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Sodium hydride (0.012 g, 0.3 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(2-hydroxyethyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole (0.100 g, 0.2 mmol) in dry tetrahydrofuran, and stirred under an atmosphere of nitrogen for 2 hours at 20° C. Ethyl chloroformate (0.029 g, 0.3 mmol) was added and stirring continued for 1 hour at 20° C. The mixture was then added to saturated ammonium chloride solution and ethyl acetate, and the organic layer washed with water and brine, dried (sodium sulfate), and evaporated. The residue was purified by flash column chromatography eluting with heptane/ethyl acetate (4:1) to give the title compound as a white powder (0.098 g, Compound 6, yield: 81%), 19F-NMR: −63.8, −78.6.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of 125 mg (3.8 mmol) of 1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-4-methoxy-1H-indole is O-demethylated by treating it with 15 mL of 1M BBr3 /CH2Cl2. The reaction mixture is stirred at room temperature for 5 hours and concentrated at reduced pressure. The crude product is chromatographed on silica gel and is eluted with 20% EtOAc/hexane to give 1030 mg (87% yield) of 1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-4-hydroxy-1H-indole.