Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([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][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([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)=[CH:9]2)[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.6 mmol) in dry DMF (100 ml) under nitrogen at 0° C. was added NaH (0.264 g, 60% dispersion, 6.6 mmol) and the reaction mixture warmed to room temperature and stirred for 1 hr. Tert-butyl 4-[(4-methylphenyl)sulfonyl]oxy-1-piperidinecarboxylate (2.34 g, 6.6 mmol) was added and the resulting solution heated at 95° C. for 72 hr. The reaction was quenched by careful addition of water (150 ml). Extract with EtOAc (3×100 ml) and wash with water (4×100 ml) and brine (2×100 ml). The organic solution was dried (Na2SO4), filtered and evaporated to leave a solid which was adsorbed onto silica and purified by flash silica gel column chromatography using EtOAc then 5% MeOH/EtOAc as eluent to give in F 13-22 tert-butyl4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate (1.0 g, 31%) as a white solid, m.pt. 168.5-169.5° C. Rf in 10% EtOAc/MeOH=0.4. 1H NMR (d6 DMSO, 250 MHz): δ 8.14 (1H, s), 7.38-7.49 (5H, m), 7.07-7.23 (5H, m), 6.14 (2H, bs), 4.76 (1H, m), 4.11 (2H, m), 2.93 (2H, m), 1.92-2.02 (4H, m), 1.43 (9H, s). Mass spec. C28H31O3N5 (485.2430). IR (KBr disc): 3059, 1695, 1588, 1235 cm−1.
Reaction SMILES: F[C:2](F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:27]5[CH:28]=N[CH:30]=[CH:31][C:26]=5[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.FC(F)(F)C(O)=O.[F:47][C:48]1[C:53]2[O:54][C:55]3[C:60]([C:61]4([C:65]5[CH:66]=[N:67][CH:68]=[CH:69][C:64]=5[C:63]([NH2:70])=[N:62]4)[C:52]=2[CH:51]=[C:50]([C:78]2[CH:83]=[CH:82][N:81]=[C:80]([F:84])[CH:79]=2)[N:49]=1)=[CH:59][C:58]([C:71]1[C:72]([F:77])=[N:73][CH:74]=[CH:75][CH:76]=1)=[CH:57][CH:56]=3.C(=O)=O>>[F:47][C:48]1[C:53]2[O:54][C:55]3[C:60]([C:61]4([C:65]5[CH:66]=[N:67][CH:68]=[CH:69][C:64]=5[C:63]([NH2:70])=[N:62]4)[C:52]=2[CH:51]=[C:50]([C:78]2[CH:83]=[CH:82][N:81]=[C:80]([F:84])[CH:79]=2)[N:49]=1)=[CH:59][C:58]([C:71]1[C:72]([F:77])=[N:73][CH:74]=[CH:75][CH:76]=1)=[CH:57][CH:56]=3.[O:54]1[CH2:55][CH2:60][CH:61]=[C:52]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:27]6[C:26](=[CH:31][CH:30]=[CH:2][CH:28]=6)[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:53]1
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Reactant: O=C(O)C(F)(F)F
Agent: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(-c2ccnc(F)c2)nc3F)c2cnccc21
Agent: O=C=O
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2ccccc21

Procedure:
The titled compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using 3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14d) and in step 4. 1-Fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14e, 77 mg) was subjected to chromatography using supercritical CO2 (additives 26% MeOH with 20 mM NH3) on a Chrialcel ADH column (21×250 mm, 5 μm) eluting at a flow rate 65 ml/min (100 bar pressure, 40° C. column temperature). The first peak (retention time=5.3 min) provided (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine (Example 14-A; >99% ee), and the second peak (retention time=7.0 min) provided (R)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine (Example 14-B; TFA salt; >99% ee).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].C(OC1C=CC(C)=C2C=1CCC2)C=C.C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH2:20]([C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:11])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Cc1ccc(O)c2c1CCC2
Agent: C=CCOCC=C
Agent: C=CCOc1ccc(C)c2c1CCC2
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(C)c2c(c1O)CCC2

Procedure:
Treatment of 7-methylindan-4-ol (10.00 g, 0.067 mol) with potassium carbonate (37.3 g, 0.270 mol) and allyl bromide (9.80 g, 0.081 mol) generally according to the procedure described for Intermediate 1 afforded 4-(allyloxy)-7-methylindane. Refluxing the allyl ether in mesitylene generally according to the procedure described for Intermediate 1 gave 5-allyl-7-methylindan-4-ol. Treatment of the phenyl with potassium carbonate (27.99 g, 0.203 mol) and benzyl bromide (12.70 g, 0.074 mol) generally according to the procedure described for Intermediate 1 provided 8.41 g (45%) of 5-allyl-4-(benzyloxy)-7-methylindane as a colorless oil. Rf=0.42 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C20H22O.0.3H2O: C, 84.65; H, 8.03. Found: C, 84.64; H, 7.78.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13](Br)=[C:12]([O:20][CH2:21][CH3:22])[CH:11]=2)=[CH:4][N:3]=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:11]=[C:12]([O:20][CH2:21][CH3:22])[C:13]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:26][CH3:23])[CH:11]=1)[CH3:18]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(OC)c1
Temperature: 25 °C

Procedure:
Tetrakis-triphenylphosphine-palladium (57 mg; 0.050 mmol) is suspended in dimethoxyethane (1 ml), while gassing with argon, and 2,4-diamino-5-(4-bromo-3,5-diethoxybenzyl)pyrimidine (367 mg; 1 mmol) in dimethoxyethane (6 ml) is added. After stirring for a quarter of an hour at room temperature, 3-methory-phenylboron acid (228 mg; 1.5 mmol) in ethanol (1.5 ml) is added, the mixture is stirred for a further 5 minutes at room temperature, an aqueous 2 M sodium carbonate solution (4.2 ml; 8.5 mmol) is added and the mixture is then boiled under reflux (bath temperature 85° C.) for 2.5 hours. The reaction mixture is concentrated and the residue is stirred with water and a little methanol and filtered off with suction. The filter cake is stirred with water, filtered off with suction and dried under a high vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC(=O)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butan-2-one according to Method C (Example 178). Yield: 217 mg (71%).
Reaction SMILES: CC(S([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH:9]=[CH2:10])=O)(C)C.Cl.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CO>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:18])=[O:19])=[CH:15][CH:16]=1)[CH:9]=[CH2:10])=[O:35]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C=CC(NS(=O)C(C)(C)C)c1ccc(S(=O)(=O)CCC)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CC(NC(=O)c1ccc(Cl)cc1Cl)c1ccc(S(=O)(=O)CCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-N-{1-[4-(propylsulphonyl)phenyl]prop-2-en-1-yl}propane-2-sulphinamide (213 mg, 0.62 mmol) was dissolved in methanol. Methanolic hydrogen chloride was added and the reaction mixture was stirred at room temperature for 2 h. Following concentration in vacuo the residue was suspended in dichloromethane and stirred under nitrogen. Triethylamine (0.173 mL, 1.24 mmol) was added followed by 2,4-dichlorobenzoyl chloride (87 μL, 0.62 mmol) and the reaction mixture was stirred overnight. The reaction was quenched by addition of water and satd. NaHCO3(aq). The product was extracted into ethyl acetate (×2) and then the combined organic layers washed with brine, dried (MgSO4) and concentrated. 1H NMR 5 (400 MHz, CDCl3) δ 0.99 (3H, t, J=7.4 Hz), 1.66-1.76 (2H, m), 3.00-3.04 (2H, m), 5.30-5.37 (2H, m), 5.86 (1H, t, J=6.9 Hz), 6.02-6.10 (1H, m), 7.19 (1H, d, J=7.9 Hz), 7.29 (1H, dd, J=8.5, 2.1 Hz), 7.40 (1H, d, J=1.9 Hz), 7.56 (2H, dd, J=8.3, 2.5 Hz), 7.83 (2H, d, J=8.3 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])(O)[C:6](F)([F:17])[C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.C1CCN2C(=NCCC2)CC1>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[C:6]([F:17])[C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2]
Reactant: CCN1N=C(Oc2ccc(C(F)(F)F)cc2)C(F)(F)C1(O)c1cccc(C#N)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)c(F)c1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-{1-ethyl-4,4-difluoro-5-hydroxy-3-[4-(trifluoromethyl)phenoxy]-4,5-dihydro-1H-pyrazol-5-yl}benzonitrile (crude, 2.1 g, 5.11 mmol), DCM (25.5 mL) and triethylsilane (2.45 mL, 15.3 mmol) was cooled to −78° C. and treated with BF3 etherate (1.94 mL, 15.3 mmol) in a single portion. The reaction was allowed to warm to rt overnight and checked via LCMS at 16 h. The reaction was treated with DBU (3.85 mL, 25.6 mmol) dropwise and checked via LCMS after 30 minutes, requisite product dominates. The reaction was diluted with EtOAc and washed with sat aq. NaHCO3 2×, brine, dried (MgSO4) and concentrated to afford an opaque brown residue purified via MPLC, 100 g silica, 5-35% EtOAc in heptanes to afford 3-{1-ethyl-4-fluoro-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}benzonitrile as a clear, colorless oil. MS: cal'd 376 (MH+), exp 376 (MH+).
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Solvent: Cc1ccccc1
Product: CNCc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 20 °C

Procedure:
Methylamine (g) was bubbled through a stirring solution of 2-(chloromethyl)-6-nitroquinoline (5.00 g, 22.47 mmol) in toluene (70 mL) at 0° C. The mixture was slowly warmed to 20° C. over 4 hours, concentrated to 1/2 volume, and partitioned between 10% aqueous K2CO3 /ethyl acetate. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated. Yield: 4.89 g as a brown solid which was used without purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C:5]1[CH:6]=[C:7]([CH:15](O)[CH:16]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[CH:17]=[CH2:18])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>C1COCC1>[F:12][C:11]([F:13])([F:14])[C:9]1[CH:8]=[C:7]([C@H:15]2[O:21][C:20](=[O:26])[NH:19][C@H:16]2[CH:17]=[CH2:18])[CH:6]=[C:5]([C:4]([F:3])([F:28])[F:29])[CH:10]=1
Reactant: C=CC(NC(=O)OC(C)(C)C)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 30.7 %

Procedure:
At 0° C. under N2, NaH (20 g, 0.500 mol) was added slowly to the mixture of tert-butyl {1-[3,5-bis(trifluoromethyl)phenyl]-1-hydroxybut-3-en-2-yl}carbamate (100 g, 0.250 mol) in anhydrous THF (1.5 L) while stirring. After the addition, the mixture was stirred at 0° C. for 1 hour, then at 80° C. for 2-6 hrs. (Caution: The mixture was stirred and heated at 80° C. for 0.5-1 hour of bubbling). The resulting mixture was cooled to 0° C. and MeOH (0.1 L) and ice water (0.2 L) was added carefully to quench the reaction. The mixture was concentrated and then diluted with ethyl acetate (2 L), washed with water (0.5 L×3), brine (0.5 L), dried and concentrated to give a black oil. Flash chromatography on silica gel yielded the crude product which was recrystallized from ethyl acetate, dichloromethane and petroleum ether to provide cis-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (25 g) as a white solid. The resultant solid was separated by chiral SFC (column—OJ 250 mm×50 mm, 10 um; mobile phase-A: supercritical CO2, B: IPA, A:B=85:15 at 230 mL/min; column temp: 38° C.; nozzle pressure-100 bar; nozzle temp-60° C.; evaporator temp-20° C.; trimmer temp-25° C.; wavelength-220 nm). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.10 (s, 1H), 7.93 (s, 2H), 6.05-6.03 (d, 1H), 5.27-5.11 (m, 2H), 4.99-4.97 (d, 1H), 4.76-4.73 (t, 1H).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:20]([CH3:40])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>ClCCl.[Zn+2].[Br-].[Br-]>[Si:33]([O:32][CH2:31][C@H:21]1[NH:22][CH2:23][C@H:18]([N:5]([O:4][CH2:1][CH:2]=[CH2:3])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:19]=[C:20]1[CH3:40])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-3-[N-(prop-2-en-1-yloxy)(2-nitrobenzene)sulfonamido]-1,2,3,6-tetrahydropyridine-1-carboxylate (Intermediate 80, 13.6 g, 22.75 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of ZnBr2 (10.2 g, 45.29 mmol, 2.00 equiv) in several batches. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 2×200 mL of sodium bicarbonate (aq) and 2×200 mL of NH4Cl (aq). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12 g (crude product) of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To the product of Example 3 (0.37 g, 0.0007 mole) in H2O (10 ml) was added LiOH (80 mg, 0.002 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ≃3 with TFA and the product was isolated by RPHPLC to yield β-[[2-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]-amino]acetyl]amino]benzenepropanoic acid, trifluoroacetate salt (280 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([NH:5][CH2:6][CH2:7][C@:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([NH2:12])[CH2:9][CH:10]=[CH2:11])[CH3:4].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:9]([C@:8]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][N:5]([C@H:3]([C:2]([CH3:20])([CH3:1])[CH3:21])[CH3:4])[C:30](=[O:32])[NH:12]1)[CH:10]=[CH2:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC[C@@](N)(CCN[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Reaction time: 2 h
Yield: 131.6 %

Procedure:
To a solution of (R)—N1—((S)-3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (600 mg, 2.05 mmol) and triethylamine (1.04 g, 10.25 mmol) in CH2Cl2 (10 mL) was added triphosgene (203 mg, 0.68 mmol) at 0° C., and the mixture was stirred for 2 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (285 mg, 44%). 1H NMR (CDCl3): 0.72 (s, 9H), 1.01 (d, 3H), 1.79 (m, 1H), 2.06 (m, 1H), 2.34 (m, 1H), 2.56 (m, 1H), 2.73 (m, 1H), 3.03 (m, 1H), 4.49 (m, 1H), 4.92 (5, 1H), 5.04-5.13 (m, 2H), 5.26 (m, 1H), 6.95-6.99 (m, 2H), 7.22-7.25 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.CN.[C:16]([NH:24][C:25](N)=[NH:26])(=O)C1C=CC=CC=1.Cl>C(O)C>[CH3:16][NH:24][C:25]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[NH:26]
Reactant: COc1cccnc1CSCCN
Reactant: N=C(N)NC(=O)c1ccccc1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNC(=N)NCCSCc1ncccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine in ethanol is added to a stirred solution of N-benzoyl dimethyldithioimidocarbonate in ethanol and the mixture is stirred overnight at room temperature. The purified product is treated with methylamine in ethanol and the resultant benzoylguanidine is hydrolysed by refluxing with aqueous hydrochloric acid to give N-methyl-N'-[2-(3-methoxy-2-pyridylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:43][O:42][C:7]3([CH2:12][CH2:11][CH:10]([N:13]4[C:18](=[O:19])[C:17]([CH2:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]6[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=6)=[CH:23][C:22]=5[F:35])=[C:16]([CH2:36][CH2:37][CH3:38])[N:15]5[N:39]=[CH:40][N:41]=[C:14]45)[CH2:9][CH2:8]3)[O:6][CH2:5]2)[CH2:3][CH2:2]1.[C:44]([BH3-])#N.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C[Mg]Br.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C.O1CCCC1>[F:35][C:22]1[CH:23]=[C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]=1[CH2:20][C:17]1[C:18](=[O:19])[N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][CH2:5][C:4]3([CH:43]([OH:42])[CH3:44])[CH2:3][CH2:2][CH2:1]3)[CH2:12][CH2:11]2)[C:14]2[N:15]([N:39]=[CH:40][N:41]=2)[C:16]=1[CH2:36][CH2:37][CH3:38]
Reactant: [BH3-]C#N
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)CO3)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Mg]Br
Agent: O=C([O-])O
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(C(C)O)CCC3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 4′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (3.6 g), sodium cyanoborohydride (5.3 g), boron trifluoride-diethyl ether complex (3.1 mL) and tetrahydrofuran (150 mL) was stirred at 50° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in acetonitrile (30 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.4 g) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 4.5 mL) was added at room temperature. The reaction mixture was stirred for 2 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.72 g, 19%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21
Yield: 82.4 %

Procedure:
5-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (example 247, 0.128 g, 0.305 mmol) in MeOH (50 mL) was run through the H-cube for 2 h (flow rate: 0.5 mL/min; temperature: 60° C.; catalyst: 10% Pd/C (THS 01111); full hydrogen mode). The resulting solution was evaporated to dryness to give the title compound (0.106 g, 74%) as a yellow amorphous solid. MS: 422.5 (M+H+).