Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:18]>ClCCl>[CH2:10]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:9][O:18]1)[CH2:11][CH3:12]
Reactant: C=CCCCC(CCC)CCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(CCC)CCCC1CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a 250 ml flask containing 6-propylnon-1-ene (4 g, 23.76 mmol, purified by distillation) and anhydrous dichloromethane (260 mL) under nitrogen atmosphere, was added at 0° C. meta-chloroperoxybenzoic acid (77%, 10.65 g, 47.53 mmol, 2 eq) and the reaction was stirred for 20 minutes at 0° C. before warming to room temperature. The disappearance of starting material is monitored by TLC. The reaction was evaporated almost to dryness and cyclohexane (260 ml) was added and the remaining solid in the flask was extracted several times with cyclohexane. The combined organic phases were then washed with saturated aqueous sodium bicarbonate (5×25 mL). After evaporation of the solvent, the crude was purified by column chromatography (eluent dichloromethane) to give the desired product (3.86 g, 88%) as a colourless oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[O:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:24]([C@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[O:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
To a solution of tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). The resulting mixture is allowed to stand for 0.5 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml), the mixture is chromatographed on Amberlite XAD-2 using water-methanol (1:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(R)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.1 g) as colorless powder.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([OH:30])[C:26]([F:29])([F:28])[F:27].CC([O-])(C)C.[K+]>C1COCC1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:30][CH2:25][C:26]([F:29])([F:28])[F:27])/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
A mixture of the product from Example 75A (537 mg, 1.45 mmol), trifluoroethanol (87 μL, 2.18 mmol) and potassium 2-methylpropan-2-olate (2.18 mL, 2.18 mmol) in THF (10 mL) was stirred at room temperature for 3 hrs. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 258 mg (40%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.32 Hz, 3H) 1.36 (s, 9H) 1.40 (dd, J=7.63 Hz, 2H) 1.82 (m, 2H) 4.19 (t, J=7.32 Hz, 2H) 4.48 (q, J=8.54 Hz, 2H) 6.65 (s, 1H) 7.02 (d, J=8.54 Hz, 1H) 8.03 (d, J=2.75 Hz, 1H). MS (DCI/NH4) m/z 449 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[CH:9]2)C=CC=CC=1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[F:41])#[N:32]>CCOC(C)=O>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:10]2[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:8]=[CH:9]2)=[CH:35][C:34]=1[F:41])#[N:32]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cncn1Cc1ccc(C#N)c(F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propionate, as described above in Step C, (5.00 g, 12.6 mmol) and 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (2.70 g, 12.6 mmol) in EtOAc (30 mL) was heated to 50° C. for 5 hours. The mixture was allowed to cool, and the solid collected by filtration. The EtOAc filtrate was concentrated in vacuo to a volume of approximately 15 mL and then reheated to 50° C. for 3 hours, cooled, and the solid removed by filtration. The two crops of precipitated imidazolium salts were combined in MeOH (120 mL) and CHCl3 (200 mL). The aqueous layer was extracted further with CHCl3 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% MeOH—0.1% NH4OH to CH2Cl2—5% MeOH—0.5% NH4OH to yield the titled product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1>CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:3]5[CH:2]=[N:28][C:6]([CH3:7])=[CH:5][CH:4]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol) 2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (262 mg, 1.2 mmol) Cs2CO3 (650 mg, 2.0 mmol) Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1 1 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 336 (168.7 mg, yield: 36%). 1HNMR (DMSO-d6, 400 MHz): δ9.04 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.91-7.87 (m, 2H), 7.76-7.71 (m, 1H), 7.48-7.45 (m, 2H), 7.36-7.34 (m, 1H), 7.14 (s, 1H), 4.30 (s, 2H), 3.14 (s, 2H), 2.52 (s, 3H). ESI-MS: m/z=474 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([S-])c1
Reactant: CCCCCC(=O)CBr
Solvent: O
Product: CCCCCC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of 3-methoxythiophenolate (45 g) in water (100 mL) at 15° C. was added dropwise over 20 minutes 1-bromo-2-heptanone (54.4 g). The reaction was stirred for 1 hour at room temperature then was extracted with diethyl ether (2×250 mL) and the ether extracts were washed in turn with water (2×100 mL) and 1N hydrochloric acid (2×100 mL). The dried (MgSO4) organic layers were combined and evaporated to yield crude 1-(3-methoxyphenylthio)-2-heptanone (71 g). The crude 1-(3-methoxyphenylthio)-2-heptanone (65 g) was added over 30 minutes with stirring to sulfuric acid at -10° C. After 30 minutes at -5° C., the reaction mixture was diluted carefully with ice (200 g) and the resulting solid was filtered off, washed with water and dried. Crystallization of the crude product from hexane gave 18.4 g of 6-methoxy-3-pentylbenzo[b]thiophene, mp 43°-45° C. A small sample was recrystallized from hexane to provide the analytical specimen, mp 45°-47° C. Anal. Calcd for C14H18OS: C, 71.75; H, 7.74; S, 13.68 Found: C, 71.81; H, 7.60; S, 13.37
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[CH:5]=[CH:4]1)[CH3:2].[I-].[Li+].N1C(C)=CC(C)=CC=1C>CCCCCC>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc(=O)c2cnc(-c3ccc(OC)cc3)nc21
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCC
Product: CCn1ccc(=O)c2cnc(-c3ccc(O)cc3)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
C-4. 8-Ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one--A mixture containing 2.4 g of 8-ethyl-2-(4-methoxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, 8.1 g of anhydrous lithium iodide, 125 ml of collidine and one drop of dicyclohexyl-12-crown-4 was refluxed with stirring for 24 hours and then allowed to cool to room temperature. The reaction mixture was diluted with n-hexane (900 ml) to complete the precipitation of the product. The oily material that separated solidified on standing at room temperature. The solid was collected, washed with n-hexane and then dissolved in water. The water solution and washed with ether, acidified with hydrochloric acid and the resulting mixture was slurried, treated with an excess of sodium bicarbonate and again slurried. The solid was collected, washed with water and dried at 65° C. in vacuo to yield 1.85 g of 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 320°-324° C. This product was combined with 12 g of product obtained in five other runs and the combined material was suspended in about 350 ml of boiling ethanol after which dimethylformamide was added portionwise until dissolution was complete. The hot solution was treated with decolorizing charcoal, filtered, and the filtrate cooled. The separated product was collected, washed with cold ethanol and dried in vacuo at 60° C. to produce 2.6 g of 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 323°-325° C. The filtrate was stripped in vacuo, the solid residue was recrystallized from ethanoldimethylformamide to yield another 0.8 g of product, 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 321°-322° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH2:25]([P:27]([O:30]C)[O:28][CH3:29])[CH3:26]>C(#N)C>[CH2:25]([P:27]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:30])[O:28][CH3:29])[CH3:26]
Reactant: CCP(OC)OC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Product: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (1.6 g, 4.4 mmol), dimethyl ethylphosphonite (1 ml, 8.8 mmol) and acetonitrile (6 ml) is stirred at room temperature overnight. The reaction mixture is concentrated to dryness, and the residue is purified by preparative thin layer chromatography (silica gel, eluting with 10% ethyl acetate/hexane) to give methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [Na].C([O:5][C:6]1[C:15]([CH2:16][CH:17](Br)[CH2:18]Br)=[C:14]2[C:9]([C:10]([CH3:22])=[CH:11][C:12](=[O:21])[O:13]2)=[CH:8][CH:7]=1)(=O)C.Cl>C(O)C>[CH3:22][C:10]1[C:9]2[CH:8]=[CH:7][C:6]3[O:5][C:17]([CH3:18])=[CH:16][C:15]=3[C:14]=2[O:13][C:12](=[O:21])[CH:11]=1
Reactant: CC(=O)Oc1ccc2c(C)cc(=O)oc2c1CC(Br)CBr
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc2c(ccc3c(C)cc(=O)oc32)o1
Temperature: 0 °C
Yield: 87.6 %

Procedure:
A solution of sodium (29.8 g, 1.296 mol) in dry, absolute ethanol (1400 ml.) was added to 7-acetoxy-4-methyl-8-(2', 3'-dibromopropyl)coumarin (108.1 g, 0.259 mol). The mixture was allowed to reflux for one hour and 45 minutes with magnetic stirring. The cooled mixture was poured into a mixture of ice (2800 g) and 3.5% HCl (2800 ml.) and stirred. A yellow precipitate was collected by filtration, washed first with three portions (600 ml.) of 5% NaOH, second with one portion (600 ml.) of 3.5% HCl, third with three portions (600 ml.) of water, and then dried in vacuo to obtain crude 4,8-dimethylisopsoralen (48.6 g, 87.6% yield, mp. 160°-174° C.). Recrystallization from 95% ethanol (1500 ml.) gave the pure product (33.7 g, 68% recovery, 61% yield) mp. 176°-178° C. (lit.2 182°-183° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 52.7 %

Procedure:
A solution of 0.57 g (1.67 mmol) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride and 0.61 g (3.34 mmol, 2 eq) of sarcosine t-butyl ester hydrochloride in 0.51 mL of pyridine and 15 mL of chloroform was allowed to react overnight at room temperature. The reaction was concentrated in vacuo, diluted with water/ethyl acetate, neutralized with NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a yellow oil which was purified via flash chormatography using 6:1 hexane: ethyl acetate to afford 0.396 g (53%) of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate as a white solid. Electrospray Mass Spec 450.4 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:24]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=2)[CH2:22][CH2:23]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCC(CCN(Cc3ccccc3)Cc3ccccc3)CC2)nc(C)n1
Reaction time: 16 h
Yield: 49 %

Procedure:
A mixture of N,N-dibenzyl-2-(piperidin-4-yl)ethanamine trifluoroacetate (see stage 6 AMN-01) (6.372 mmol, 1.0 eq), 4-chloro-2,6-dimethylpyrimidine (1.17 g, 8.283 mmol, 1.3 eq) and K2CO3 (2.64 g, 19.116 mmol, 3.0 eq) in acetone (50 ml) was stirred for 16 hours at boiling temperature. After monitoring by TLC, the mixture was concentrated, diluted with DCM (100 ml) and washed with water (50 ml) and sat. NaCl solution (50 ml). The org. phase was dried over sodium sulfate and concentrated under reduced pressure, and the crude product so obtained was purified by column chromatography (silica gel, 2% MeOH in DCM). Yield: 49% (1.3 g, 3.14 mmol)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[CH:12][C:13]([CH:17]([CH3:20])[CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[CH:12][C:13]([CH:17]([CH3:20])[CH2:18][CH3:19])=[C:14]([CH:15]=1)[O:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CCC(C)c1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)COc1cc(C(F)(F)F)ccc1C(C)CC
Temperature: 80 °C

Procedure:
2.5 ml of ethyl bromoacetate were added to 4 g of the product of Step C in 15 ml of dimethylsulfoxide and 4 g of potassium carbonate were added, followed by heating at 80° C. for 2 hours 30 minutes. The reaction medium was poured into iced water and extracted with methylene chloride. The extracts were dried and concentrated to dryness to obtain 5.10 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C([O-])([O-])=[O:31].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
A mixture of compound 5 (100 mg, 0.3 mmol), compound 5A (89 mg, 0.6 mmol), Cs2CO3 (2 M, 0.45 mL) and Pd(PPh3)2Cl2 (10 mg) in 1,4-dioxane (5 mL) under a nitrogen atmosphere was stirred in microwave at 120° C. for 15 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified pre-TLC to give compound 6 (40 mg, yield 30%) as a white solid. 1H NMR (CDCl3 400 MHz): δ 8.05 (m, 1H), 7.87 (m, 3H), 7.72 (m, 3H), 7.60 (m, 1H), 3.69-3.75 (m, 2H), 3.17 (m, 2H), 3.01 (m, 2H), 2.30 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([CH3:18])[CH3:17])=[CH:12][C:11]=1[F:20])[CH3:9])(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[F:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([CH3:18])[CH3:17])[CH:14]=[CH:15][C:10]=1[C@@H:8]([NH2:7])[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(C)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(C(C)(C)F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a round bottom flask containing (S)-tert-butyl(1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42 mmol) was added HCl in dioxane (2.1 mL, 8.42 mmol). Resulting reaction mixture allowed to stir 1 hr at room temperature. Volatiles were removed. Et2O was then added and the mixture sonnicated briefly. Volatiles were once again removed to a afford an HCl salt of (S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine (104 mg, 0.44 mmol, 105% yield) as a white solid. 1H NMR (400 MHz, D2O) δ 1.59-1.80 (m, 9H) 7.24-7.37 (m, 2H) 7.43-7.56 (m, 1H). LCMS m/z 200.1 (M+H)+, Rt 0.54 min.
Reaction SMILES: II.[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1C=CC=CC=1.[Zn]>[CH3:3][C:4]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCCCCC(C)=O
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCCCCCC(C)(O)CC(=O)OCC
Temperature: 0 °C
Yield: 53.9 %

Procedure:
To a slurry of zinc (65.0 g, 1.0 mol) in benzene (100 ml), containing a small crystal of iodine, refluxed with stirring, was added carefully 60 ml of mixture of octan-2-one (76.8 g, 0.6 mol), ethyl bromoacetate (167.0 g, 1.0 mol) and benzene (100 ml). After initiation of the reaction, the rest of the reaction mixture was added at such a rate that reflux was maintained. After complete addition of the ketone mixture the resultant reaction mixture was boiled at reflux for a further 1 hr. The mixture was then cooled and poured into ice-cold 20% sulphuric acid (400 ml), and the mixture was extracted with diethyl ether (4×200 ml). The combined extracts were washed with water (200 ml), saturated sodium hydrogen carbonate solution (2×250 ml) and saturated sodium chloride solution until neutral. The extract was then dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give an oil. This residual oil was distilled to afford ethyl 3-methyl-3-hydroxynonanoate (70.0 g), b.pt. 88°-90° C./0.07 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C.[Zn]>[NH2:1][C:4]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude reaction mixture from 106a was dissolved in ethanol (4 mL) and ethyl acetate (1 mL). Zinc dust (1.3 g, 20 mmol) was added to the mixture along with ammonium chloride (300 mg, 5.7 mmol). The mixture was shaken at rt for 18 h. The reaction mixture was filtered over Celite®, and concentrated to afford mainly 106b which was used in the next step without further purification. [M+H]+=212.32.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)NC1CCCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
9.9 PARTS OF CYCLOHEXYLAMINE IS DISSOLVED IN 100 PARTS OF BENZENE AND THE MIXTURE IS REACTED WITH 15.5 PARTS OF 2-METHYLBENZOYL CHLORIDE IN THE PRESENCE OF 12 PARTS OF TRIETHYLAMINE AT 10°C. The whole is stirred for 3 hours at 60°C and then cooled; the precipitated triethylamine chloride is filtered, the filtrate is concentrated under vacuum and the residue is recrystallized from a mixture of methanol and water.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH2:26][C:22]3([CH3:27])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CCCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].