Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[C:41]([C:40]1[NH:36][C:37]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=2[N:22]2[CH2:23][C@H:24]([OH:28])[C@@H:25]([OH:27])[CH2:26]2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:38][CH:39]=1)#[N:42]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2C[C@H](O)[C@@H](O)C2)[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 28.1, 100 mg, 0.217 mmol), (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1, 103 mg, 0.436 mmol), Pd(PPh3)2Cl2 (15.22 mg, 0.022 mmol), Na2CO3 (92 mg, 0.867 mmol), DME (920 μL), water (263 μL) and EtOH (131 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 90 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH-1% NH4OH, from 1% to 10% MeOH-1% NH4OH) followed by preparative SFC (Column NH2, from 26% to 31% in 10 min) to yield the title compound as an off-white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=473.2 [M+H]+, m/z=471.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.76 Hz, 2H) 3.26-3.32 (m, 2H) 3.89 (br. s, 2H) 5.08 (d, J=2.93 Hz, 2H) 6.24 (d, J=3.67 Hz, 1H) 6.84 (d, J=8.93 Hz, 1H) 7.00 (d, J=3.67 Hz, 1H) 7.33 (d, J=8.44 Hz, 2H) 7.84-7.93 (m, 4H) 10.10 (s, 1H) 12.52 (br. s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][CH2:14][CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCOc1cccc(OC)c1C=O
Reaction time: 18 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (3.74 g, 0.025 M), ethyl 5-bromo-2,2-dimethylpentanoate (5.95 g, 0.025 M), anhydrous potassium carbonate (3.72 g), sodium iodide (0.11 g) and ethanol (50 ml) were refluxed with stirring for 18 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give ethyl 5-(2-formyl-3-methoxyphenoxy)-2,2-dimethylpentanoate, 6.46 g, 84%, as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14]N(C)CC1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:2][CH2:3][N:9]2[CH3:10])[C:2]=1[F:1])=[O:21]
Reactant: CN1CCC(Nc2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: CN1CCCCC1Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1F
Yield: 155.8 %

Procedure:
Mix 2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg) in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g of the title compound (78% yield): mass spectrum (ion spray): m/z=380 (M+1); 1H NMR (CDCl3): 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd, 1H), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:20])=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=O)=[CH:4][CH:3]=1.[CH2:21]1COCC1.C[Mg]Cl>CC(=O)OCC>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:20])=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[CH2:21])=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)c3cc(Br)ccc3oc2c(F)c1F
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Product: C=C1c2cc(Br)ccc2Oc2c1cc(OC)c(F)c2F
Temperature: -10 °C

Procedure:
A solution of 7-bromo-3,4-difluoro-2-methoxy-9H-xanthen-9-one (8.25 g, 24.19 mmol) in THF (242 mL, 24.19 mmol) was cooled to −40° C. To the resulting slurry was added methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (24.19 mL, 72.6 mmol), leading to the formation of a slightly darker mixture. After slowly warming to −10° C. over the course of 30 min TLC showed the clean conversion to a slightly more polar product (1:1 EA in hexanes). The reaction was removed from the cold bath and quenched with saturated ammonium chloride (500 mL). This mixture was poured into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with 200 mL of 10% citric acid then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 7-bromo-3,4-difluoro-2-methoxy-9-methylene-9H-xanthene as a bright yellow solid that was used immediately. To a solution of iodine (8.98 g, 35.4 mmol) in 150 mL of THF at −25° C. was added silver cyanate (15.91 g, 106 mmol). The reaction was maintained at this temperature for 15 min at which time a solution of 7-bromo-3,4-difluoro-2-methoxy-9-methylene-9H-xanthene (12.0 g, 35.4 mmol) in 3 mL of THF was added. The reaction temperature rose to −15° C. during this addition. The reaction was maintained at −25° C. for 45 min at which time ammonia, 2.0 M solution in 2-propanol (106 mL, 212 mmol) was added. The reaction was allowed to warm to rt and was maintained at that temperature overnight. The reaction was filtered through a pad of celite, washing well with ethyl acetate. This solution was diluted with 10% sodium thiosulfate (1000 mL) and poured into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a light yellow foam. This solid was suspended in 100 mL of CH2Cl2 and 100 mL of ether was added. The slurry was filtered to provide 6.0 g of a light yellow solid. The filtrate was concentrated and purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-100% CH2Cl2 to 10:1 methanol in CH2Cl2 with 0.1% ammonium hydroxide) to provide 7′-bromo-3′,4′-difluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an orange solid (7.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) in EtOH (100 ml) was treated with SnCl2.2H2O (25.61 g, 110.2 mmol) and the resulting mixture heated at 70° C. under an atmosphere of Nitrogen for 5 h. The reaction mixture was then cooled to rt and treated with ice-water (50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixture was then extracted with EtOAc (3×150 ml) and the combined extracts washed with brine (3×100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=2.68 (s, 3H), 4.74 (brs, 3H), 6.27 (d, 1H, J=8.4 Hz), 6.61 (dd, 1H, J=2.0 & 8.4 Hz) and 6.66 (d, 1H, J=2.0 Hz). MS (ES+): m/z 201.10 and 203.12 [MH+].
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:3])[CH3:2].[Br:15]Br.C(N(CC)CC)C>CCOCC.O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([Br:15])[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CCCCCCSC=CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCSC(Br)=CCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hexylthio-2-propenyl acetate (1.3 g, 6.0 mmol) in 10 ml of ether cooled to -10° is added bromine (1.05 g, 0.34 ml, 6.6 mmol). The mixture is stirred at ambient temperature for 30 min., then cooled to 0° and triethylamine (3.0 g, 4.18 ml, 30.0 mmol) is added. The reaction mixture is stirred overnight at RT, then diluted with water and extracted with hexane. The extract is washed with 2N H2SO4, water, saturated NaHCO3 and brine and is dried. The crude product is purified by prep. TLC on silica gel eluting with 20% ethyl acetate/hexane. The upper band is collected to give 3-bromo-3-hexylthio-2-propenyl acetate. The lower band is collected to give 2-bromo-3-hexylthio-2propenyl acetate.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N=C=NCCCN(C)C)C.[CH3:36][O:37][CH2:38][CH2:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:23][CH2:24]4)=[CH:20][C:16]([C:17]([NH:43][S:40]([CH2:39][CH2:38][O:37][CH3:36])(=[O:42])=[O:41])=[O:19])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Reactant: COCCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.3 %

Procedure:
A mixture of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid (0.24 g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g, 1.83 mmol), 4-dimethylaminopyridine (0.22 g, 1.83 mmol), and 2-methoxyethanesulfonamide (0.13 g, 0.95 mmol) in dichloromethane (10 mL) was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL), brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.25 g, 76%): 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 3.93 (s, 2H), 3.75-3.65 (m, 4H), 3.14 (s, 3H), 2.07-1.98 (m, 1H), 1.98-1.91 (m, 3H), 1.73-1.58 (m, 12H) 0.99-0.91 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Br)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100 g, 0.378 mmol) and 5-(4-bromophenyl)thiophene-2-carbaldehyde (0.101 g, 0.378 mmol) in acetic acid 5 mL is added β-alanine (3.37 mg, 0.038 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.120 g, 0.234 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.84 (m, 1H), 7.63 (m, 1H), 7.50 (m, 3H), 7.15 (m, 6H), 6.69 (s, 1H), 5.66 (dd, J=11.4, 5.1 Hz, 1H), 3.69 (dd, J=14.4, 12.0 Hz, 1H), 3.51 (dd, J=10.5, 5.1 Hz, 1H). MS (ES+, m/z): 511.3 (M−−1, 100.0).
Reaction SMILES: [O-]CC.[Na+].C(OCC)(=O)CC(OCC)=O.CS([O:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)(=O)=O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl>O.C(O)C>[OH:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: CC[O-]
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: O
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
Preparation B: A reactor, maintained under a nitrogen atmosphere, was charged with 200 proof ethanol (5.50 kg) and 21% (by weight) sodium ethoxide in ethanol (7.00 kg, 21.6 mol). The mixture was stirred and warmed to 30° C. Diethyl malonate (3.50 kg, 21.9 mol) was added over a 20 min period. The reaction mixture was then warmed at 40° C. for 1.5 h. A solution of tert-butyl (R)-3-(methylsulfonyloxyl)pyrrolidine-1-carboxylate (3.00 kg of the product from Example 2, Procedure B, 10.7 mol) in 200 proof ethanol (5.50 kg) was added, and the resulting mixture was heated at reflux (78° C.) for 2 h. Both GC and TLC analysis (ninhydrin stain) indicated that no starting material remained. The stirred mixture was then cooled to 25° C., diluted with water (2.25 kg), and treated slowly with a solution of concentrated hydrochloric acid (1.27 kg, 12.9 mol) in water (5.44 kg). This mixture was washed twice with methyl tert-butyl ether (MTBE) (14.1 kg and 11.4 kg), using 15 min of stirring and 15 min of settling time for each wash. The combined MTBE washes were dried over anhydrous sodium sulfate (1 kg), filtered and concentrated under vacuum at 50° C. for 6 h. The residue (red oil) weighed 4.45 kg and was 49% desired product by GC analysis (62% overall yield from tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: COc1ccccc1-c1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1c(N)nc2ccc(C(=O)c3ccccc3)cn12

Procedure:
The 2-trifluoroacetamido-3-(2-methoxyphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (7.40 g, 16.8 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.0 g. (87%). EA, MS(FD).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C1CCCCC1>O.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(N)ccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Temperature: 35 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A 50 liter jacketed glass reactor was fitted with an N2 inlet, a mechanical stirrer, and a condenser. With the stirrer set to 150 rpm and the jacket temperature set at 40° C., 2-Me-THF (6.000 L, 3.0 vol), 2-fluoro-4-(trifluoromethyl)benzoic acid (2000 g, 9.610 mol), 2-methoxypyridin-4-amine (1.278 kg, 10.09 mol), and TEA (2.917 kg, 4.018 L, 28.83 mol) were added to the reactor, which resulted in a slightly hazy, light amber solution. The reactor was switched to reaction control and heated to 35° C. To the solution was added T3P in 2-Me-THF (9.176 kg, 9.176 L of 50% w/w, 14.42 mol) over 30-45 min, which resulted in a light amber solution. After 2 hours, the reaction was judged to be complete by HPLC analysis (<2% of 1 remaining). The reaction was quenched with water (1.000 L, 0.5 vol), which was added via addition funnel over a period of 10 minutes in order to control the exothermic quenching reaction. The mixture was then diluted with 2-Me-THF (8.000 L, 4.0 vol) and water (8.000 L, 4.0 vol) and stirred for 30 minutes at 30-40° C. After stirring was stopped, the layers were allowed to separate, and the aqueous layer was removed. The organic layer was washed with 10% aqueous NaOH (6.000 L, 3.0 vol), stirring resulted in an emulsion. Brine (500.0 mL, 0.25 vol) was added, and the mixture was stirred for about 5 minutes. The layers were separated, and the aqueous layer removed. The organic layer was washed again with brine (10.00 L, 5.0 vol), and the aqueous layer was drained. The organic layer was dried over Na2SO4, and filtered through diatomaceous earth (Celite). The filter cake was washed with 2-Me-THF (4.000 L, 2.0 vol) and pulled dry. The filtrate was transferred to a rotovap, and partial distillation of solvent was begun at a bath temperature of 40° C. and a pressure of 150 mbar, resulting in the formation of solids in the mixture. Cyclohexane (10.00 L, 5.0 vol) was added portionwise during the partial distillation. Distillation was stopped, the reaction mixture (˜8 liter) was slurried on the rotovap, and the bath temperature was reduced to room temperature. The mixture was filtered, and the filter cake was washed with cyclohexane (2.000 L, 1.0 vol) and pulled dry under a nitrogen blanket to afford a light yellow solid. The solid was scooped out of the funnel and dried in vacuo (40° C., <30 mbar, rotovap) to afford 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (2,501 g, 7.959 mol, 83%) as a fine, off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (Example 4(c), 67 mg, 0.22 mmol), lithium hydroxide monohydrate (55 mg, 1.3 mmol), water (2 mL), and dioxane (2 mL) was stirred at 110° C. for 1.5 hr and then concentrated. The residue was partitioned between water (4 mL) and diethyl ether (6 mL) were added. The ether layer was reextracted with water (1 mL). The combined aqueous solutions were neutralized with aqueous 10% citric acid solution to pH=5 and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were washed with brine (2 mL), dried (Na2SO4) and concentrated to give 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoic acid (57 mg, 0.20 mmol, 89% yield). MS found: (M−H)−=288.19.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[I-].[C:18]([Si:22]([CH3:39])([CH3:38])[O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30](N2C=C[N+](C)=C2)=[O:31])[CH2:26][CH2:25]1)([CH3:21])([CH3:20])[CH3:19].N12CCN(CC1)CC2>CN(C)C=O>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:38])[CH3:39])[CH2:25][CH2:26]2)=[O:31])=[N:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccc1
Reactant: C[n+]1ccn(C(=O)N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1
Agent: C1CN2CCN1CC2
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Temperature: 40 °C
Yield: 79.9 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (214 mg, 1.00 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (451 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in dimethylformamide (10 mL) was stirred for 18 hours at room temperature followed by heating for 3 days at 40° C. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60), yielding the title compound (364 mg, 77% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9](OCC)=[O:10])([O-:3])=[O:2].Cl.CN.[CH:20]([N:23](C(C)C)CC)(C)C>CO.O>[CH3:20][NH:23][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Agent: CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-nitrophenoxyacetate (9.12 g, 40 mmol), methylamine hydrochloride (26.8 g, 400 mmol) and diisopropylethylamine (35.5 mL, 200 mL) in MeOH (100 mL) was stirred in a pressure vial at 90° C. for 6 h. The reaction was cooled to room temperature, diluted with water (1 liter), the solid formed was filtered, washed with water and dried to get the desired N-methyl 3-nitrophenoxyacetamide (8 g, 95%). 1H NMR CDCl3): δ 7.91 (dd, 1H, J=1.8 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.50 (t, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=1.8 and 8.4 Hz), 6.50 (bs, 2H), 4.57 (s, 2H), 2.95 and 2.93 (2s, 3H); LCMS: ret. time: 17.54 min.; purity: 100%; MS (m/e): 211 (MH+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: Ic1cccnc1
Product: c1cncc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)c1
Yield: 18 %

Procedure:
The title compound (28 mg, 18%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 3-iodopyridine similarly to the procedure used for example 153. 1H NMR (400 MHz, CDCl3) δ 1.66-1.94 (m, 8H), 2.01-2.06 (m, 4H), 2.17-2.20 (m, 4H), 2.60-2.68 (m, 2H), 2.76 (m, 1H), 3.22-3.27 (m, 3H), 3.57 (t, 2H), 3.77-3.81 (m, 2H), 4.32 (m, 1H), 6.73 (d, 1H), 6.92 (d, 2H), 6.99 (m, 1H), 7.23 (d, 2H), 7.88 (m, 2H). HRMS ESI+ m/z 422.2789 [MH]+.