Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[C:8]([NH:11][C:12]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([F:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[CH3:9].C(O)(=O)C>CCCCCC.CO.C1C=CC=CC=1>[CH3:3][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([F:24])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:12]=1[NH:11][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1cc(F)c([N+](=O)[O-])cc1NC(C)=O
Reaction time: 0.25 h
Yield: 86 %

Procedure:
2.06 ml (4.12 mmol) of a 2M solution of diazomethyl-trimethyl-silane in hexane are added with slight cooling at 20° C. to a solution of 1.0 g (4.13 mmol) of 2-acetylamino-5-fluoro-4-nitro-benzoic acid in 15 ml of methanol and 35 ml of benzene. HPLC analysis after 15 minutes shows that there are still about 50% of the starting material present. Additional 2.4 ml (4.8 mmol) of the diazomethyl-trimethyl-silane solution are added. After standing for about 16 hours, no starting material can be detected by HPLC. 0.5 ml of glacial acetic acid are added and the reaction mixture is evaporated to dryness. Toluene is added and the mixture is again evaporated. The resulting residue is dissolved in refluxing ethyl acetate, hexane is added, the formed crystals are filtered, washed with hexane and dried at about 0.01 torr and 50° C. yielding 912 mg (86%) of 2-acetylamino-5-fluoro-4-nitro-benzoic acid methyl ester, m.p. 124-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=469.1, tR (minutes, Method G)=2.54. [α]D20=+27.60 (c=3.20 mg/mL,CHCl3)
Reaction SMILES: C[Si](OC)(OC)OC.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:21]([NH2:16])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:13][CH2:14][CH2:9][CH2:10][CH2:11][CH2:12][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:9][CH3:15]
Reactant: Cc1ccccc1
Reactant: c1ccncc1
Agent: CO[Si](C)(OC)OC
Product: CCCCCCCCCCCCCCCCCCN

Procedure:
Fractogel phosphate (1; 5 g) containing a trace amount of pyridine was slurried with octadecylamine (6 g) and left at 60° C. for 2 days. Toluene (100 ml) was added to the flask and the mixture refluxed for 24 hours. The mixture was then filtered and the gel washed with methanol to yield Fractogel C-18 (4). The resin was capped with methyltrimethoxy silane in toluene-pyridine at 60° C. for 24 hours. Analysis showed; C, 48.82; H, 6.26; N, 5 1.34%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([C:15]#[N:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:15][NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ccc(F)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Cyano-(4-fluoro-phenyl)-acetic acid tert-butyl ester (3.78 g) was mixed with Raney nickel (5 mL, 50% water) in MeOH (100 mL) and stirred under hydrogen balloon at rt overnight. The mixture was then filtered through Celite, concentrated to give crude, which was silica gel column purified to give 3-amino-2-(4-fluoro-phenyl)-propionic acid tert-butyl ester (1.3 g).
Reaction SMILES: C(N=S(C1C=CC(CN[C:13]([C:15]2[C:20](=[O:21])[C:19]([Br:22])=[C:18]([CH3:23])[N:17]([C:24]3[N:25]([CH3:29])[N:26]=[CH:27][CH:28]=3)[CH:16]=2)=[O:14])=CC=1)(C)=O)#N.C(N=S(C1C=CC(CN[C:44](C2C(=O)C=C(C)N(C3N(C)N=CC=3)C=2)=[O:45])=CC=1)(C)=O)#N.BrBr>>[CH3:44][O:45][C:13]([C:15]1[C:20](=[O:21])[C:19]([Br:22])=[C:18]([CH3:23])[N:17]([C:24]2[N:25]([CH3:29])[N:26]=[CH:27][CH:28]=2)[CH:16]=1)=[O:14]
Reactant: Cc1cc(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Agent: BrBr
Product: COC(=O)c1cn(-c2ccnn2C)c(C)c(Br)c1=O

Procedure:
The title compound is prepared as described for preparation 4c, substituting preparation 4b with preparation 8.20a as starting material. ESI mass spectrum: [M+H]+=326 (bromine pattern); r.t. HPLC: 0.69 min (Z012_S04).
Reaction SMILES: N[C:2]1C=CC2N(CCN)N=C3C4C=CC=CC=4S[C:3]=1C=23.[NH2:21][C:22]1[CH:30]=[CH:29][C:28]2[N:27]([CH2:31][CH2:32][NH:33][C:34](=O)[CH3:35])[N:26]=[C:25]3[C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[S:39][C:23]=1[C:24]=23>>[NH2:21][C:22]1[CH:30]=[CH:29][C:28]2[N:27]([CH2:31][CH2:32][N:33]([CH2:2][CH3:3])[CH2:34][CH3:35])[N:26]=[C:25]3[C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[S:39][C:23]=1[C:24]=23
Reactant: CC(=O)NCCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Reactant: NCCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2

Procedure:
5-amino-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, mp 131°-140° C., hydrochloride salt, mp greater than 300° C. N-[2-(5-amino-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)ethyl]acetamide, mp 213°-216° C., hydrochloride salt, mp 287° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[O:16][C:15]([F:14])([F:25])[F:26])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3OC(F)(F)F)ccc12
Yield: 19.2 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 2-(trifluoromethoxy)benzylamine (122 mg, 0.636 mmol), Pd2(dba)3 (49 mg, 0.0535 mmol), rac-BINAP (104 mg, 0.167 mmol) and NaOtBu (142 mg, 1.478 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-trifluoromethoxy-benzylamino)-2H-phthalazin-1-one (41 mg) as a beige solid, 1H (400 MHz, d6-DMSO) δ: 4.50 (s, 2H), 6.78 (s, 1H), 7.16 (dd, 1H), 7.40 (m, 3H), 7.47 (d, 1H), 7.68 (t, 1H)m 7.95 (d, 1H), 12.37 (s, 1H) ppm; m/z (M+1) 369.86.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:30])[CH3:29])[S:7][C:6]=2[CH:31]=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Si:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:29])[CH3:30])[S:7][C:6]=2[CH:31]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccccc1-c1sc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a solution of (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (100 mg, 0.232 mmol) in DCM (3 mL) at room temperature were added tert-butyldimethylsilyl chloride (88 mg, 0.581 mmol) and N,N-diisopropylethylamine (0.122 mL, 0.697 mmol). The resulting mixture was stirred at room temperature for 18 h after which time the reaction was quenched by addition of water and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting crude material was then dissolved in THF (wet) and K2CO3 (32.1 mg, 0.232 mmol) was added and the mixture was stirred at room temperature for 2 h. Upon completion the reaction was quenched by addition of 1N HCl and extracted with EtOAc (2×), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (120 mg, 0.220 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66 (d, J=16.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.34-7.24 (m, 5H), 7.17-7.09 (m, 1H), 6.90-6.82 (m, 3H), 6.26 (d, J=15.9 Hz, 1H), 3.24 (p, J=6.7 Hz, 1H), 1.17 (d, J=6.7 Hz, 6H), 1.01 (s, 9 H), 0.24 (s, 6H).
Reaction SMILES: C([O:3][P:4]([O:32]CC)(/[C:6](=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])C.Br[Si](C)(C)C.CC(C)=O.CCCCCCC.O>C(Cl)Cl.CC(C)=O>[P:4](/[C:6](=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[C:7]([O:9][CH2:10][CH3:11])=[O:8])([OH:32])([OH:5])=[O:3]
Reactant: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OCC)P(=O)(O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
Ethyl 2-(diethoxyphosphinyl)-3-[2-(1-tridecynyl)phenyl]-2-E-propenoate (0.50 g, 1.02 mmol) prepared according to Example 5 was dissolved in dry CH2Cl2 (3 ml) and CD2Cl2 (2 ml, dried over activated neutral alumina) and cooled to 0° C. Bromotrimethylsilane (0.31 ml, 2.35 mmol) was added over a two to three minute period. The progress of the reaction was monitored by 31 p NMR, to follow disappearance of the starting material. After about 5 hours, the solvent was removed under reduced pressure. Acetone-heptane (5.5 ml, 10:1) containing 0.045 ml (2.5 mmol) water was added and the reaction was stirred for 1.5 hours. At the end of this time the solvent was stripped. Since NMR indicated incomplete reaction, acetone (5 ml) containing water (0.05 ml, 2.8 mmol) was added and stirring was continued for two hours. After stripping the solvent, the reaction was still incomplete. It required 2.5 more hours under these conditions to complete the reaction. The solvent was stripped off and the residue was chromatographed on silica eluting with 10% chloroform and 20% methanol in heptane. Fractions containing product were recrystallized from heptane yielding a white solid, 0.211 g, 0.486 mmol, 47.6% yield; mp 68°-69° C.; 1H NMR (CDCl3) ∂0.86 (m, 3H), 1.09 to 1.63 (several m, 21H), 2.40 (t, J=7.1 Hz, 2H), 4.19 (q, J=7.1 Hz, 2H), 7.17 to 7.44 (several m, 4H), 8.15 (d, J=24.7 Hz, 1H), 8.81 (br s, 2.7H); FAB mass spectrum m/z 434 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C@:14]2([CH3:21])[CH2:19][CH2:18][O:17][C:16]([NH2:20])=[N:15]2)[CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C@:14]3([CH3:21])[CH2:19][CH2:18][O:17][C:16]([NH2:20])=[N:15]3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@]1(c2cc(N)ccc2F)CCOC(N)=N1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(NC3CCCC3)ccc2F)CCOC(N)=N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.4 %

Procedure:
A solution of cyclopentanone (26.2 μl, 296 μmol) and (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (60 mg, 269 μmol) in dichloromethane (2 ml) was treated with acetic acid (30.8 μl, 538 μmol) followed by sodium triacetoxyborohydride (85.4 mg, 403 μmol). The reaction mixture was stirred at room temperature for 2.5 hours. For the workup, the reaction mixture was quenched with a saturated solution of sodium hydrogencarbonate, then extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on a silica-NH2 phase using a gradient of n-hexane/ethyl acetate=50:50 to 0:100 as the eluent to yield the (S)-4-(5-cyclopentylamino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (5 mg, 6% yield). MS (ISP): m/z=292.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15]O>>[CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([O:11][CH3:15])=[O:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Product: COC(=O)C(O)c1ccc(C(C)C)cc1

Procedure:
To a solution of 4-isopropylmandelic acid (17 g) in methanol (150 ml) was added Dowex-50X-400® and the mixture was refluxed for 4 hours. After cooling it was filtered through Celite® and the filtrate was evaporated to give a syrupy residue of methyl 4-isopropylmandelate (18.9 g), which solidified upon storing at room temperature.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[Cl:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:13]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: O=CC(Cl)C=O
Solvent: CC(=O)O
Product: OCc1nc2ncc(Cl)cn2n1
Temperature: 80 °C

Procedure:
To a slurry of (3-amino-1H-1,2,4-triazol-5-yl)methanol (28.5 g, 150 mmol) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction to room temperature, the product crystallized out as a white solid (25.5 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 4.67 (s, 2 H), 5.62 (s, 1 H), 8.94 (d, J=2.45 Hz, 1 H), 9.81 (d, J=2.45 Hz, 1 H). MS (APCI): 185.0 (M+H+).
Reaction SMILES: C([N:8]1[C:12]2([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:11]2[CH2:10][O:9]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:8][C:12]1([C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:18])[CH3:19])[CH2:15][CH:11]1[CH2:10][OH:9]
Reactant: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CON4Cc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc(-c2cccc(C3(N)CC(O[Si](C)(C)C(C)(C)C)CC3CO)c2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1-benzyl-5-(tert-butyldimethylsilyloxy)-6a-(3′-methoxybiphenyl-3-yl)hexahydro-1H-cyclopenta[c]isoxazole (2.04 g, 3.76 mmol) and palladium on carbon (0.400 g) in acetic acid (10 mL) is stirred at room temperature under hydrogen atmosphere (50 psi) for 19 hours. The reaction is filtered through a pad of diatomaceous earth and the filter cake is washed with methanol three times and the filtrate is concentrated under reduced pressure. The residue is dissolved in dichloromethane, the pH adjusted to pH 12 by addition of saturated aqueous sodium bicarbonate, and is extracted three times with dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. ES/MS m/e: 428 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:18]([F:29])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]=2[CH:6]=1)=O.[BH4-].[Na+]>CCO.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:19]2[C:5]([CH2:3][OH:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[N:9][C:8]=3[C:18]=2[F:29])=[C:22]([Cl:28])[CH:23]=1
Reactant: COC(=O)c1cc2c(ncn2CCS(C)(=O)=O)c(F)c1Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(CO)cc21
Reaction time: 96 h
Yield: 79.5 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11cc (0.300 g, 0.594 mmol) is suspended in a mixture of EtOH (6 mL) and THF (4 mL) under N2. NaBH4 (0.112 g, 2.97 mmol) is added. After approximately 4 days stirring, reaction mixture is quenched by the addition of AcOH until the reaction mixture reaches pH 7. The reaction mixture is concentrated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with water (3×), brine, and dried (Na2SO4). The organic layer is concentrated under reduced pressure until a white precipitate forms which is collected by filtration to give 0.225 g (79%) clean desired product: LC/MS ESI (+) m/z 478, 476 (M+ Br pattern) detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24]CC)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Temperature: 90 °C
Yield: 85.9 %

Procedure:
(R)-ethyl 5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.76 g, 2.14 mmol) was suspended in EtOH (10.7 mL) and the mixture was heated at 90° C. for 20 minutes (homogeneous). 1M aqueous LiOH (4.29 ml, 4.29 mmol) was added and the reaction mixture was heated for 15 hours at 90° C. After cooling, the reaction mixture was concentrated, diluted with water and washed with EtOAc to remove any unreacted starting material. The aqueous layer was then acidified to pH 4 using 2N HCl. After extracting with DCM and EtOAc, the combined organic layers were dried with MgSO4, filtered and concentrated to afford (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.60 g, 85.7% yield) as a glassy yellow solid. MS (apci) m/z=327.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>CN(C=O)C>[C:6]([NH:8][CH2:9][C:10]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:12])([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(O)CO
Reaction time: 18 h
Yield: 98 %

Procedure:
10.00 g (36.73 mmol) Boc-Gly-Osu (Bachem) was dissolved together with 3.35 g (36.77 mmol) 1-amino-2,3-propanediol in 50 ml DMF and stirred for 18 h. The product was purified by flash chromatography (CH2Cl2 /MeOH; 95:5 v/v). 8.94 g (98%) 19 was obtained as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]2[O:26][CH:25]=[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36](=[O:46])[CH2:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:31][CH2:30]4)[C:5]=2[C:6]([N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:7][CH:8]=1)#[N:2].Cl.O1CCOCC1>>[NH2:9][C:6]1[C:5]2[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36](=[O:46])[CH2:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:31][CH2:30]4)=[CH:25][O:26][C:4]=2[C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#N)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnc(N)c2c(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)coc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.2 %

Procedure:
A mixture of bis(1,1-dimethylethyl) (7-cyano-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-yl)imidodicarbonate (359 mg, 3:2 mixture with non-Boc as described above) and 4.0 M HCl in dioxane (3.0 mL, 12.00 mmol) was stirred at room temperature under Nitrogen for 14 hr. The mixture was concentrated in vacuo and taken up in EtOAc (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (1×50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2, 15%-85% EtOAc in hexanes gradient over 52 minutes) to give 4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridine-7-carbonitrile (118 mg, 45.7% yield) as a white solid. LC/MS (ES) m/z=431 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.28 (t, 2H), 3.97 (s, 2H), 4.30 (t, J=8.46 Hz, 2H), 6.57 (br. s., 2H), 7.14-7.33 (m, 4H), 7.40 (s, 1H), 8.09-8.17 (m, 2H), 8.38 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][O:41]C1C=CC(CN)=CC=1>>[CH2:34]([CH:26]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[C:25]([NH:24][CH:15]1[CH:14]2[C:13](=[O:39])[CH2:12][CH:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][C:5]([O:41][CH3:40])=[CH:6][CH:7]=3)[CH2:23][N:21]3[C:22]2=[C:18]([CH:19]=[CH:20]3)[CH2:17][CH2:16]1)=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Reactant: COc1ccc(CN)cc1
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccc(OC)cc1)C3
Yield: 40 %

Procedure:
The compound of Example 3d was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using 4-methoxybenzylamine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.53 mmol/g) and purification by RP-HPLC provided 12.0 mg (40%) of the title compound as a white powder. MS (M+H)+=563.43.
Reaction SMILES: O[CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.N1C=CC=CC=1.S(Cl)([Cl:38])=O>C(Cl)(Cl)Cl>[Cl:38][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCCCCCCCCCC(O)CCCCCNc1ccc(C(=O)OCC)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(Cl)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A solution of 10 g. of ethyl 4-(6-hydroxyhexadecylamino)benzoate and 2.4 ml. of pyridine in 50 ml. of chloroform is treated with 2.0 ml. of thionyl chloride, stirred under reflux for 1 hour, washed with 1 N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated. The residue is crystallized from aqueous ethanol to yield the product as a white solid.