Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Si:25]([O:42][CH2:43][CH2:44][C@@H:45](O)[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Si:25]([O:42][CH2:43][CH2:44][C@H:45]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:46])([C:38]([CH3:39])([CH3:40])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a tetrahydrofuran solution (24 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (Example 1-3) (968 mg) were added at room temperature (2S)-4-{[tert-butyl(diphenyl)silyl]oxy}butan-2-ol (1.48 g), triphenylphosphine (1.18 g) and di-tert-butyl azodicarboxylate (1.04 g), followed by stirring overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford benzyl 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylate (2.25 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5].Cl.C(N(C(C)C)CC)(C)C.[CH3:23][N:24]=[C:25]=[O:26]>ClCCl>[CH3:23][NH:24][C:25]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7]1)=[O:26]
Reactant: CN=C=O
Reactant: CCOC(=O)C1CNCCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)NC)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol) was suspended in dichloromethane (7 ml), diisopropylethylamine (180 μl; 0.99 mmol) was added, followed by commercially available methyl isocyanate and (57 μl; 0.98 mmol). This mixture was stirred at ambient temperature for approximately 3 hours, and then diluted with fresh dichloromethane and washed with water. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure, giving ethyl 1-(N-methylaminocarbonyl)-4-oxo-3-piperidinecarboxylate (74.4 mg) as a white solid. MS m/z (positive ion) 479 (dimer+Na+; 40), 457 (dimer+; 25), 251 (M+Na+; 100), 229 (MH+; 90), 205 (25), 130 (25).
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].O.NC1N=C2C(N=CN2[CH:29]2[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2([Cl:43])[Cl:42])=C(Cl)N=1>CS(C)=O>[Cl:11][C:30]([Cl:42])([Cl:43])[CH:29]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C1(C(=O)OCC)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OCC
Temperature: 25 °C
Yield: 82.8 %

Procedure:
In a one-liter four-necked flask, 50.0 g (294.9 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 88.2 g (648.0 mmol) of potassium carbonate were added to 650 ml of dimethylsulfoxide, and 26.1 g (1449.9 mmol) of water was then added to the resulting mixture. The resulting mixture was stirred at room temperature. Next, 127.4 g (440.0 mmol) of diethyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for two hours and a half at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were collected by filtration, washed with 100 ml of water, and then dried under reduced pressure, to give 101.5 g (240.1 mmol) of white crystals of 2-amino-6-chloro-9-(3,3-dicarboethoxy-2,2-dichlorocyclopropyl)purine. The yield was 82.8%.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:18])(C)(C)C>O1CCOCC1>[ClH:1].[CH3:18][C:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13][C:9]=1[NH2:8]
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N)sc2ccccc12
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A 5-L 3-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with 4M HCl in dioxane (3.1 L), compound 306-B (265 g, 1.0 mol) and stirred for 18 h at 22° C. The white precipitate was collected by filtration, washed with diethyl ether (3×500 mL), and dried under house vacuum at 40° C. for 48 h to afford 174 g of compound 757-A as a white solid. 1H-NMR (DMSO-d6): δ 8.7 (br s, 3H), 7.71 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.14 (t, 1H), 2.184 (s, 3H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.C(O[C@@H:22]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:23]1[O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C>C(#N)C>[C:25]([O:24][C@@H:23]1[C@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:43]([CH2:45][O:46][C:47](=[O:54])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[O:44][C@H:22]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 58 %

Procedure:
0.56 g. (5 mmol) of uracil was agitated in 70 ml. of absolute acetonitrile with 1.86 g. (3.5 mmol) of HMDS and 2.55 g. (15.5 mmol) of TCS, as well as 1.69 g. (12 mmol) of NaClO4.H2O for 30 minutes at 24° C. The reaction mixture was then combined with 2.52 g. (5 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose and refluxed for 20 hours. The mixture was worked up as described in Example 1, yielding 58% of crystalline uridine tribenzoate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH2:16][CH2:17][CH3:18])[N:13]=[C:12]([NH:19][C:20](=[O:28])OC3C=CC=CC=3)[N:11]=2)[CH2:6][CH2:5]1>ClCCl>[CH3:1][N:2]([CH3:3])[C:20]([NH:19][C:12]1[N:11]=[C:10]([N:7]2[CH2:6][CH2:5][O:4][CH2:9][CH2:8]2)[N:15]=[C:14]([CH2:16][CH2:17][CH3:18])[N:13]=1)=[O:28]
Reactant: CCCc1nc(NC(=O)Oc2ccccc2)nc(N2CCOCC2)n1
Reactant: CNC
Solvent: ClCCl
Product: CCCc1nc(NC(=O)N(C)C)nc(N2CCOCC2)n1
Reaction time: 12 h
Yield: 39.9 %

Procedure:
A gaseous stream of dimethylamine is passed through a solution of 5 g (0.0145 mole) of phenyl (4-morpholino-6-propyl-1,3,5-triazin-2-yl)carbamate (compound 28 prepared in example 3) in 100 ml of anhydrous dichloromethane for three hours at a temperature of 20° C. The mixture is then allowed to stand for 12 hours. It is washed successively with a dilute sodium hydroxide solution and with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue obtained crystallizes in a 50:50mixture (v/v) of ethyl acetate-hexane. 1.7 g of N,N-dimethyl-N'-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-urea is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[CH3:41][NH:42][C:43](=[O:46])[CH2:44][NH2:45]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([NH:45][CH2:44][C:43]([NH:42][CH3:41])=[O:46])=[O:27])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: CNC(=O)CN
Product: CNC(=O)CNC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and N1-methylglycinamide with System A used for purification by mass directed autopreparation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 47.3 %

Procedure:
To a solution of 3-Chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (186.1) (0.980 g) and NH4Cl (1.64 g) in EtOH (50 ml)-H2O (5 ml), was added iron powder (1.92 g). The mixture was heated to reflux for 1 hr. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat. NaHCO3 and extacted with AcOEt (30 ml×3). The combined organic layeres were washed with brine and dried over Na2SO4. Concentration of solvent afford crude product, which was purified by column chromatography (silicagel, AcOEt:Hexane=1:3) to provide aniline 186.2 (0.420 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:19]=1)=[O:7]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (500 mg), N-(4-aminophenyl)morpholine (385 mg), EDAC (828 mg), HOBT (583 mg) and N-methylmorpholine (714 μl) in DMF (5 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (818 mg)
Reaction SMILES: [CH3:1][C:2]1([C:14]([O-:16])=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Li+].CC([N-]C(C)C)C.CCCCCCC.C1C[O:35][CH2:34]C1.[CH2:37](C1C=CC=CC=1)C.BrCOC>C1COCC1>[CH3:34][O:35][CH2:1][C:2]1([C:14]([O:16][CH3:37])=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])C1
Reactant: C1CCOC1
Reactant: CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: COCBr
Agent: [Li+]
Solvent: CCCCCCC
Product: COCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
The title compound was prepared according to general procedure A described in connection with Scheme 2. 1-tert-Butyl 3-methylpyrrolidine-1,3-dicarboxylate (7.27 g, 31.7 mmol) was dissolved in 80 mL of THF under argon. 2M LDA in heptane/THF/Ethylbenzene (19 mL, 38 mmol) was added in 30 min. between −78° C. and −68° C. The reaction mixture was stirred at −78° C. for 45 min. Neat bromo(methoxy)methane (5.25 g, 41.2 mmol) was added over 11 min. at −78° C. The reaction was slowly warmed to RT and stirred for 20 h. The reaction mixture was cooled to −20° C. and quenched with 50 mL 10% NH4Cl. The aqueous layer was extracted with 50 mL EtOAc. The organic layer was washed with 50 mL brine and then dried over Na2SO4. The solvent was evaporated and the resulting residue was purified by 2 flash chromatographies on silica gel using Hexanes/EtOAc 10:1 to 2:1 and 1/3 to give 4.5 g (52% yield) of the desired product. MS (ESI) m/z: Calculated for C13H23NO5: 273.2. found: 295 (M+Na)+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH2:20])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:3].[CH3:21][C:22]1[N:26]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[O:24][N:23]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[C:25]2[O:24][N:23]=[C:22]([CH3:21])[N:26]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:3]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1

Procedure:
A solution of (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg, 1.64 mmol), 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 335 mg, 1.64 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (335 mg, 2.46 mmol), EDC (472 mg, 2.46 mmol) and triethylamine (0.687 ml, 4.92 mmol) in DCM (5 ml) was stirred at room temperature for 16 hours. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile) and recrystalised from MTBE/heptane to afford the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[O:40]=[C:41]1[O:45][N:44]=[C:43]([C:46]2[CH:47]=[C:48]3[C:58](=[CH:59][CH:60]=2)[O:57][C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][C:49]3=[O:61])[NH:42]1>CN(C=O)C.O.CCN(CC)CC>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([N:54]4[CH2:55][CH2:56][C:51]5([CH2:50][C:49](=[O:61])[C:48]6[C:58](=[CH:59][CH:60]=[C:46]([C:43]7[NH:42][C:41](=[O:40])[O:45][N:44]=7)[CH:47]=6)[O:57]5)[CH2:52][CH2:53]4)=[O:36])[CH:32]=3)[CH:27]=[CH:26]2)[CH2:23][CH2:24]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4noc(=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (58 μL), HOBT (32 mg) and WSC (40 mg) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indol-6-carboxylic acid (40 mg) and 6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (70 mg) in DMF (4 mL), and stirred overnight at room temperature. Water was added to the reaction mixture, and the formed solid was collected by filtration. The solid was washed thoroughly with water and ether. This was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 12.91 (1H, brs), 8.20 (1H, d, J=4.0 Hz), 8.00 (1H, dd, J=8.0, 4.0 Hz), 7.36-7.26 (2H, m), 7.22 (1H, s), 6.57 (1H, s), 6.39 (1H, d, J=4.0 Hz), 4.20-4.00 (1H, m), 3.87 (3H, s), 3.46-3.40 (1H, m), 3.40-3.20 (3H, m), 2.89 (2H, s), 2.06-1.77 (4H, m), 1.07-1.03 (2H, m), 0.94-0.90 (2H, m); MS [M+H]+=515.
Reaction SMILES: [H][H].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:22]([OH:23])[CH2:21][C:20]3[C:19]([OH:24])=[CH:18][C:17]([OH:25])=[CH:16][C:15]=3[O:14]2)=[CH:9][C:8]=1[OH:26])[CH:4]=[CH2:5]>[Pd].C(O)C>[OH:26][C:8]1[CH:9]=[C:10]([CH:13]2[CH:22]([OH:23])[CH2:21][C:20]3[C:19]([OH:24])=[CH:18][C:17]([OH:25])=[CH:16][C:15]=3[O:14]2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:3][CH2:4][CH3:5]
Reactant: C=CCOc1ccc(C2Oc3cc(O)cc(O)c3CC2O)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(C2Oc3cc(O)cc(O)c3CC2O)cc1O
Reaction time: 3 h

Procedure:
To a suspension of 10% palladium on carbon (5 mg, 10 mol %) in 5 mL ethanol which had been stirred vigorously under 1 atmosphere of hydrogen for 10 minutes then cooled with an ice/methanol bath was added a solution of 2-(4-Allyloxy-3-hydroxy-phenyl)-chroman-3,5,7-triol (50 mg) in 2 mL ethanol. The ice bath was removed and the reaction was stirred for 3 h under 1 atmosphere of hydrogen. The mixture was passed through a 0.22 micron nylon syringe filter and concentrated to a foam which was dissolved in acetonitrile/water, frozen, and lyophilized give 2-(3-Hydroxy-4-propoxy-phenyl)-chroman-3,5,7-triol as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=O)[CH2:3][C:4]([OH:6])=[O:5].[Cl-].C([O:21][C:22](=[O:33])CCCCCCCC(O)=O)C.C(OC(=O)C=C(C)C)C>>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:22]([OH:33])=[O:21])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(CCCCCCCCC(=O)O)CC(=O)O
Reactant: CCOC(=O)CCCCCCCC(=O)O
Agent: CCOC(=O)C=C(C)C
Agent: [Cl-]
Product: CC(CCCCCCCCCC(=O)O)CC(=O)O

Procedure:
The starting material 3-methyl-tridecanedioic acid (m.p.68.5°-69.5° C.) is prepared, under the conditions described in Example 1 for the preparation of 3-methyldodecanedioic acid, from azelaic acid ethyl ester chloride and dimethylacrylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[Br-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>C1COCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1ccn2nc(Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (100 mg, 0.34 mmol) and Tetrakis (392 mg, 0.034 mmol) in THF was heated to 80° C. for 0.5 hrs before 2,4 difluoro benzyl zinc bromide was added. The reaction was complete after 0.5 hrs, cooled to ambient temperature, and diluted with H2O and EtOAc. The organic layer was extracted with EtOAc, H2O, brine, dried over MgSO4, and concentrated to a solid. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:10]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:10])=[O:8]
Reactant: [NH4+]
Reactant: O=C1CCCCCO1
Agent: [OH-]
Product: NC(=O)CCCCCO

Procedure:
ε-Caprolactone was charged to a flask equipped with a mechanical stirrer and thermometer and cooled in an ice bath to below 5° C. A pre-cooled 30% solution of ammonium hydroxide was added and the reaction temperature was maintained below 5° C. until all ε-caprolactone was consumed as indicated by gas chromatography. The water and excess ammonia were vacuum stripped at 50° C. at the completion of which the acid value was measured to be 2300. The acid by-product was removed via flocculation by addition of lithium hydroxide hydrate in methanol solution and ethyl acetate followed by isopropanol until clarified. A second portion of ethyl acetate was added and the flocculated acid was filtered. All solvents were stripped under reduced pressure at 50° C. to yield 6-hydroxycaproamide (2750 g) as a pale yellow oil which crystallized upon standing at room temperature. Gas chromatographic and NMR spectral data indicated greater than 95% purity.
Reaction SMILES: [Cl:1][C:2]1C=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CC[N:12](CC)CC.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>CC#N>[Cl:1][C:2]1[N:12]=[C:6]([NH:20][CH:17]2[CH2:19][CH2:18]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)cc1Cl
Reactant: NC1CC1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: Fc1cnc(Cl)nc1NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To 2,4 dichloro-5-fluoropyridine (1 g, 6 mmol) dissolved in CH3CN (8 ml) cooled in an ice bath was added Et3N (1.16 ml, 8.4 mmol) and cyclopropylamine (0.29 ml, 8.4 mmol) in CH3CN (2 ml). Reaction stirred 0° C. for 2 hours, evaporated water added and reaction extracted with EtOAc (×3). The organic fractions were combined washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (0.92 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(OC)(C)(C)C>[CH:13]1([CH2:12][O:11][C:3]2[CH:4]=[C:5]([F:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH2:15][CH2:14]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Br)c(OCC2CC2)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reaction time: 1 h

Procedure:
A stirred solution of 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methoxy-benzene from example A19 (27.51 g; 0.10 mol) in dry tert-butylmethylether (500 mL) is cooled to −20° C. before addition of n-butyl lithium (1.6 M in hexane; 68.8 mL; 0.11 mol) via syringe. After complete addition stirring is continued for one hour. Neat 2-iso-propoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane is added via syringe into the reaction mixture at −40° C. After 30 min the reaction is quenched with 1M citric acid (200 mL) at 0° C. and stirred for one hour at ambient temperature. The organic layer is separated. The aqueous layer is extracted with tert-butylmethylether (100 mL). The combined organic layers are washed with brine (200 mL) dried over MgSO4 and filtered through a plug of neutral alumina containing 5 wt % of water. The product is completely eluted with several small portions of tert-butylmethylether. The solvent is removed under reduced pressure. The crude is purified by short path distillation at 3×10−3 mbar (160° C.) to give the title compound as a colorless oil that solidifies at ambient temperature. Yield: 22.65 g.