Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=3)[C:6]2=[O:22])[CH2:3][CH2:2]1.[CH2:23](O)[CH2:24][CH2:25][CH3:26].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:23]([O:20][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[C:6](=[O:22])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2c(=O)n1CC1CC1
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 2-cyclopropylmethyl-6-fluoro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.16 g, 30 mmol), 1-butanol (3.3 mL, 45 mmol) and tributylphosphine (14.9 mL, 60 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (15.14 g, 60 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-2-cyclopropylmethyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.24 g, 85.2%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH:21]=[N:20][N:19]=[N:18]1>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[N:19]=[N:20][CH:21]=[N:17]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Yield: 24 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (20 g), potassium carbonate (23.5 g) and 1H-tetrazole (12 g) in dimethylformamide (60 ml) was heated to 100° under nitrogen for 24 h. On cooling, the solvent was evaporated and the residue taken up in water, extracted with dichloromethane (4×100 ml), dried (Na2SO4) and evaporated to give an orange solid. This was purified by FCC (cyclohexane/ethyl acetate (3:1)) to give the title compound as a solid (6.5 g). T.l.c. (Cyclohexane/ethyl acetate (3:10), Rf 0.43.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:31]=[CH:30][C:19]4[C:20]([C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)=[O:25])=[C:21]([CH3:23])[O:22][C:18]=4[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.[CH3:32][NH2:33]>C1COCC1.CS(C)=O>[CH:27]1([NH:26][C:24]([C:20]2[C:19]3[CH:30]=[CH:31][C:16]([O:15][C:9]4[C:8]5[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][NH:33][CH3:32])=[CH:6][CH:7]=5)[N:12]=[CH:11][CH:10]=4)=[CH:17][C:18]=3[O:22][C:21]=2[CH3:23])=[O:25])[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc2c1C(=O)NC1CC1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNCCOc1ccc2c(Oc3ccc4c(C(=O)NC5CC5)c(C)oc4c3)ccnc2c1

Procedure:
A solution of compound 90-1 (100 mg, 0.21 mmol) and 0.3 ml of methylamine 90-J (R′═CH3, R′═H) in THF (2N) in DMSO (2 ml) was heated to 60° C. for 1 hour. The reaction mixture was purified by HPLC (Dionex System) using 10-50% CH3CN/H2O+0.1% AcOH over 30 minutes to give N-cyclopropyl-2-methyl-6-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide 90 (42 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[NH:76][NH:75][C:74](=[O:77])[N:73]=2)=[CH:68][CH:67]=1>CN(C=O)C>[O:77]=[C:74]1[NH:75][NH:76][C:72]([C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:30])=[CH:67][CH:68]=2)=[N:73]1
Reactant: Nc1ccc(-c2nc(=O)[nH][nH]2)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nc(=O)[nH][nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (264 mg, 0.56 mmol) in DMF (5 mL), HATU (Aldrich, 213 mg, 0.56 mmol) was added followed by the addition of DIPEA (0.1 mL) and 5-(4-amino-phenyl)-1,2-dihydro-[1,2,4]triazol-3-one (made above, 100 mg, 0.56 mmol). The mixture was stirred at rt for 4 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5% MeOH/methylene chloride) to give a white solid. 47 mg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:28])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.O>C1COCC1>[F:28][C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=2)=[CH:13][CH:14]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
Into a 100 mL single-neck flask, 49 mg of acetyl chloride was added dropwise to 200 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (prepared in example 5) and 63 mg of triethylamine in THF (25 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 193 mg as a foam. This material was purified via silica gel chromatography employing the Chromatotron, using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 to yield the title compound (121 mg, 54%) as a white foam. Ion spray M.S. 391.2 (M*−1).
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[N:7][C:6]=2[C:5]2=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:17](=[O:19])[CH2:18][CH:4]2[CH2:3]1.O=S(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:26][CH:2]1[C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[N:7][C:6]=2[C:5]2=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:17](=[O:19])[CH2:18][CH:4]2[CH2:3]1
Reactant: C[Si](C)(C)C1=C2c3nc4ccccc4cc3C(O)CC2CC1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)C1=C2c3nc4ccccc4cc3C(Cl)CC2CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The 5-hydroxy-1-trimethylsilanyl-3,3a,4,5-tetrahydro-2H-cyclopenta[c]acridin-2-one (323 mg, 1.00 mmol) is dissolved in 10 ml of freshly distilled DCM under an argon atmosphere at 0° C. SOCl2 (182 μl, 2.5 mmol) is then added dropwise to the reaction medium, which is stirred at 0° C. for 15 min. The reaction medium is then run into a saturated aqueous solution of NaHCO3, the aqueous phase is extracted with DCM and the resulting organic phase is rinsed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and evaporated. The residue obtained is purified by flash chromatography.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].C(=O)(O)[O-].[Na+].[NH:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:19]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(COC)OC.O1CCCC1>[NH:18]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@H:19]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:24])[CH:20]([CH3:21])[CH3:22]
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Citrulline (2.54 g, 14.50 mmole) and Sodium Bicarbonate (1.28 g) in water (40 mL) was added Boc-Val-OSu (4.34 g, 13.81 mmole) dissolved in dimethoxyethane (DME). To aid the solubility of the mixture tetrahydrofuran (10 mL) was added. The mixture thus obtained was let stir overnight at room temperature. Aqueous citric acid (15%, 75 mL) was added and the mixture was extracted with 10% 2-propanol/ethyl acetate (2×100 mL). The organic layer was washed with brine (2×150 mL) and the solvents were removed on the rotovap. The resulting white solid was dried in vacuo for 5 hours and then treated with ether (100 mL). After brief sonication and trituration, the white solid product was collected by filtration (1.39 g, 27%). 1H NMR (CD3OD)δ 0.91 (dd, 3H), 0.98 (dd, 3H), 1.44 (s, 9H), 1.70 (m, 2H), 1.87 (m, 2H), 2.02 (m, 2H), 3.11 (t, 2H), 3.89 (t, 1H), 4.39 (q, 1H), 8.22 (d, 1H) ppm; LC-MS (ESI) 375 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:29]4[CH:30]=[CH:31][N:32]=[C:27]([CH3:26])[N:28]=4)[CH2:24][CH2:25]3)=[O:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1nccc(Cl)n1
Reactant: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nccc(N2CCN(C(=O)C3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1

Procedure:
The crude 1-(4-chlorophenylsulphonyl)-4-(piperazin-4-ylcarbonyl)piperidine hydrochloride, 2-methyl-4-chloro-pyrimidine (299 mg) and triethylamine (1.47 ml) were heated under reflux in ethanol (12 ml) for 5 hours. The solvent was removed by evaporation. Purification by filtration column chromatography (silica) eluting with 2% methanol/dichloromethane increasing to 10% methanol/dichloromethane gave 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperidine as a solid (0.87 g); NMR (CDCl3): 1.7-2.0 (m, 5H), 2.5 (m, 5H), 3.5-3.8 (m, 10H), 6.3 (m, 1H), 7.5 (m, 2H), 7.7 (m, 2H), 8.2 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][C:10]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=2)[CH2:27][S:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH:4]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>ClCCl>[N:15]1([C:13]2[CH:12]=[CH:11][C:10]([NH:21][C:22]([C:24]3[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=3)[CH2:27][S:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])=[C:9]([C:5]3[CH:4]=[C:3]([C:2](=[O:1])[C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)[CH:8]=[CH:7][N:6]=3)[CH:14]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(O)c3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
A −10° C. solution of 23 mg of tert-butyl 3-((3-((2-(4-(hydroxy(3-(trifluoromethyl)phenyl)methyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzyl)thio)propanoate 5.2d, 17 mg of diisopropylethylamine, and 10 mg of DMSO in 0.4 mL of dichloromethane was treated with 10 mg of pyridine sulfur trioxide complex. After stirring for 1 h the reaction mixture was applied directly to a silica gel column and eluted with a gradient of 0% to 10% ethyl acetate in dichloromethane. Evaporation of the solvent yielded 9.5 mg of product. MS (ES, m/z) 704.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]1[C:7]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:6]([F:12])[CH:5]=[CH:4][C:3]1([CH2:14][O:15][CH3:16])[OH:13].[Li]CCCC.[CH3:22][S:23]SC>C1COCC1>[F:1][CH:2]1[C:7]([Si:8]([CH3:9])([CH3:10])[CH3:11])=[C:6]([F:12])[CH:5]=[C:4]([S:23][CH3:22])[C:3]1([CH2:14][O:15][CH3:16])[OH:13]
Reactant: CSSC
Reactant: COCC1(O)C=CC(F)=C([Si](C)(C)C)C1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(O)C(SC)=CC(F)=C([Si](C)(C)C)C1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 67.7 %

Procedure:
A flame-dried 3-necked flask was charged with 2,4-difluoro-3-trimethylsilyl-1-methoxymethylphenol (27, 0.63 g, 2.56 mmol) in 15 mL of freshly distilled THF under argon and this mixture was cooled to −78° C. (FIG. 2E). nBuLi (2.5 M solution in hexane, 1.16 mL, 2.9 mmol) was added to this reaction mixture which was allowed to stir at −78° C. for 2.5 h under argon. Methyldisulfide (0.27 g, 2.9 mmol) was then added to the mixture at −78° C. and then the acetone/dry ice bath was removed and the reaction was allowed to proceed at room temperature for 14 hours. Sat. NH4Cl (˜10 mL) was added to the mixture which was then stirred for an additional 10 min and then extracted with ethyl ether (3×10 mL). The combined organic solution was washed with brine, water and then dried (MgSO4) and filtered. The solvent was removed under vacuo to afford the product purified by flash chromatography on silica gel (EtOAc:hexanes; 5:95) to yield a yellow oil (0.51 g, 68%). 1H NMR (CDCl3) δ6.55-6.58 (dd, 1 H, ArH), 5.09 (s, 2 H, CH2), 3.63 (s, 3 H, CH3), 2.41 (s, 3 H, CH3), 0.34-0.35 (t, 9 H, Si(CH3)3); FAB-MS 293 (MH+, 24), 292 (M+, 70), 262 (66), 261 (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:13])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1.[CH3:18]I>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([O:13][CH3:18])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1
Reactant: CI
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1OC

Procedure:
3,5-Diallyl-4-methoxybenzoic acid methyl ester was prepared from 3,5-diallyl-4-hydroxybenzoic acid methyl ester and methyl iodide following Method C. The resulting product was used without further purification.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9]([OH:11])=[O:10])=O)C.OC12CC3CC(CC(C(=O)C(O)=O)(C3)C1)C2>>[NH2:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=C(O)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Product: N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
U.S. application Ser. No. 10/716,012 filed Nov. 18, 2003 discloses a method for preparing (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid which utilizes 3-hydroxy-α-oxotricyclo[3.3.1.13,7]-decane-1-acetic acid as a starting material and wherein an enzymatic reductive amination is used to prepare and isolate (αS)-α-amino-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid which is converted to the desired product in a separate step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31]>O1CCOCC1.CS(C)=O.C(OCC)(=O)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]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 150 °C
Yield: 32.2 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.378 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 3, 0.41 g), tri-tert-butylphosphinium tetrafluoroborate (0.023 g), tris-(dibenzylideneacetone)dipalladium (0.036 g) in dioxane (6 mL) and DMSO (0.6 mL) was sealed in a microwave vial, under nitrogen and heated at 150° C. in the microwave for 45 minutes. After cooling, the mixture was diluted with ethyl acetate and water, the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.13 g) as a brown foam. This material was used without further characterisation.
Reaction SMILES: [CH2:1]([Li])CCC.N#N.C(NC(C)C)(C)C.[NH:15]1[CH:19]=[N:18][C:17]([CH2:20][C:21]2([CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]2)[C:22]#[N:23])=[N:16]1.CI>O1CCCC1>[NH:15]1[CH:19]=[N:18][C:17]([CH:20]([C:21]2([CH:24]=[CH:25][CH:26]=[CH:27][CH2:28]2)[C:22]#[N:23])[CH3:1])=[N:16]1
Reactant: [Li]CCCC
Reactant: N#CC1(Cc2nc[nH]n2)C=CC=CC1
Agent: N#N
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1nc[nH]n1)C1(C#N)C=CC=CC1
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (25 mL of 2.1M reagent in hexane, 0.0525 mole) is added dropwise in an N2 atmosphere to a solution of di-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which is maintained at -20°. This cold solution is then added dropwise to a solution of 4-[1-(1,2,4-triazolylmethyl)benzonitrile (9.10 g) in tetrahydrofuran (250 mL) which is maintained at -50° during addition and for 30 minutes subsequently. The reaction mixture is then cooled to -70° and 7.1 g (3.1 mL) of methyl iodide is added dropwise. The reaction is stirred at -70° for 30 minutes and then without external cooling for 10 hours. The reaction is quenched by addition of water (300 mL) and extracted with diethyl ether (3×100 mL). The combined ether extracts are extracted with 3N hydrochloric acid (3×60 mL) and the acid extracts are made basic (pH 9) with 6N sodium hydroxide. The crude product is extracted into ether (3×60 mL), and after drying (MgSO4) and solvent evaporation, 4-[1-(1-(1,2,4-triazolyl)ethyl]benzonitrile is obtained.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].C(Cl)(=O)C1C=CC=C(C(Cl)=O)C=1.[F:25][C:26]([F:38])([C:29]([F:37])([F:36])[C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH2:27][OH:28]>>[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][C:11](=[O:12])[O:28][CH2:27][C:26]([F:38])([F:25])[C:29]([F:36])([F:37])[C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])=[C:8]=[O:9]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O=C=NCCCCCCN=C=O
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Product: O=C=NCCCCCCNC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F

Procedure:
399 g of hexamethylene diisocyanate (HDI) were initially introduced at 80° C. in a 1 l round-bottomed flask and 0.002 g of isophthaloyl dichloride was added. 73.4 g of 2,2,3,3,4,4,5,5-octafluoropentanol were slowly added dropwise and stirring was effected until the NCO value was 39.4% by weight. The mixture was separated by distillation on a thin-film evaporator and 40 g (=40% of theory) of the title compound having an NCO content of 12.4% by weight were obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([F:18])[CH:16]=2)[N:11]=[CH:10][C:9]1=[O:20].Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:19][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[F:18])[N:8]([CH2:7][CH2:6][CH:2]=[O:1])[C:9](=[O:20])[CH:10]=[N:11]2
Reactant: O=c1cnc2cc(F)c(F)cc2n1CCC1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CCCn1c(=O)cnc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)ethyl]-6,7-difluoroquinoxalin-2(1H)one (0.6 g, 2.1 mmol) in dioxane (10 ml) was added 4N hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 4 hours. An aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was dried in vacuum and used as such for the next step. 0.3 g (59%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12]>>[CH3:17][Si:15]([CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCCCCCO
Yield: 52.6 %

Procedure:
Using the procedure of Step A of Preparation 16, 8.12 g of sodium hydride at 50% in oil, 20 g of 1,6-hexane diol and 25.5 g of tertbutyl dimethyl chloro silane were reacted to obtain after chromatography, 20.7 g of the expected product.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]3[CH:18]=[C:17]([Cl:19])[N:16]=[N:15][C:14]=3Cl)=[CH:11][N:10]=[C:9]([NH2:21])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[NH4+].[Cl-].C(O)(C(F)(F)F)=O>CS(C)=O.C(#N)C.O>[Cl:19][C:17]1[N:16]=[N:15][C:14]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]3[N:8]=[C:9]([NH2:21])[N:10]=[CH:11][C:12]=3[C:13]=2[CH:18]=1
Reactant: Nc1ncc(-c2cc(Cl)nnc2Cl)c(NC2CCCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncc2c3cc(Cl)nnc3n(C3CCCC3)c2n1
Temperature: 110 °C
Reaction time: 3.33 h
Yield: 6.3 %

Procedure:
A mixture of crude N4-cyclopentyl-5-(3,6-dichloropyridazin-4-yl)pyrimidine-2,4-diamine (323) (0.27 g, 0.83 mmol) and sodium bicarbonate (0.065 mL, 1.7 mmol) in DMSO (10 mL) was heated in an oil bath at 110° C. for 11 h. Then the temperature was raised to 125° C. and stirred at this temperature for 200 min at which time LC-MS showed completion. Upon workup, the mixture was poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (3×). The combined organics were washed with saturated NH4Cl aqueous solution (1×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM). The impure product thus obtained was subjected to subjected to preparative reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each). After lyophilization, 15 mg of compound 322 was obtained as a TFA salt as an off-white solid. 1H NMR (400 MHz, CD3OD) δ ppm 9.06 (1 H, s), 8.21 (1 H, s), 5.50 (1 H, quin, J=8.6 Hz), 2.43-2.60 (2 H, m), 1.99-2.25 (4 H, m), 1.71-1.89 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 289.1.