Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=O.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)C>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 81 %

Procedure:
25.7 g (0.1 mol) of 2-nitro-2'-hydroxy-5'-methylazobenzene, 0.125 g of palladium carbon, 100 ml of toluene, 50 ml of IPA, 25 ml of water and 7 g of 50% dimethylamine were charged into a 500-ml stainless autoclave with an agitator. After the air in the flask had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. Reaction was then effected in the same way as that employed in Example 1. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 81% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The toluene layer was separated, and most part of toluene was then distilled off from the layer. The residual solid was then crystallized using ethanol and then dried to obtain 15.7 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (yield, 69.8%; melting point, 128° to 130° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:31])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=C(C)ON=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C[O:27]CC1.C([Li])CCC.C(=O)=O>O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Reactant: C1CCOC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole (326 mg, 0.99 mmol) was charged to an oven-dried 100 mL 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, rubber septum and a magnetic stirring bar. Anhydrous THF (35 mL) was added, and the solution was cooled to -78° C. under a dry nitrogen blanket. To this solution, n-butyllithium (1.6 N in hexane; 0.74 mL) was added, via syringe over approximately 3 minutes, keeping the reaction temperature <-75° C. The deep red suspension was stirred at -78° C. for 1 hour. Simultaneously, anhydrous tetrahydrofuran (80 mL) was cooled to -78° C. in an oven-dried 250 mL round-bottom flask. This solvent was saturated with carbon dioxide gas. The red reaction solution was quenched into the carbon dioxide-saturated THF. The yellow reaction was warmed to room temperature over 2 hours, then diluted with water (50 mL) and ether (80 mL). The solution was extracted with aqueous sodium hydroxide (5%, 2×50 mL), and the combined aqueous solution was acidified to pH <2 with aqueous hydrochloric acid (conc.). The acidic solution was extracted with dichloromethane (2×50 mL). The combined organic solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to a crude solid. The solid was dissolved in methanol (20 mL) in a 100 mL round-bottom flask equipped with a magnetic stirring bar and a nitrogen gas inlet. Oxone® (2.13 g, 3.47 mmol) and water (3 mL) were added, the suspension was stirred at room temperature for 2 hours, warmed to reflux and held for an additional 2 hours. Upon cooling to room temperature, water (35 mL) and aqueous hydrochloric acid (6 N, 1 mL) were added. The resulting suspension was cooled to 0° C., held for 30 minutes, filtered and washed with cold water to yield, upon drying, [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid as white crystals (173 mg, 43%): mp 89° C. Mass spectrum: MH+=406. Anal. Calc'd. for C19H16NO6FS: C, 56.29; H, 3.98; N, 3.46; S, 7.91. Found: C, 56.22; H, 4.00; N, 3.44; S, 7.85.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:19])=[CH:10][CH:9]=1>CN(C=O)C.COC(C)(C)C>[C:1]([O:4][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[O:19])[NH:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(CBr)c2ccccc12
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)c2ccccc12
Yield: 55.3 %

Procedure:
A mixed solution of sodium acetate (1.1 g), 4-(bromomethyl)-N-[(trimethylsilyl)methyl]naphthalen-1-carboxamide (2.5 g) in DMF (30 ml) was stirred for 3 hours at 70° C. The reaction mixture was returned to room temperature and diluted with t-butyl methyl ether. The mixture was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain (4{[(trimethylsilyl)methyl]carbamoyl}naphthalen-1-yl)methyl acetate (1.3 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCC(C)(C)C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 31.2 %

Procedure:
Using a method similar to Example 405, using 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 3,3-dimethylbutylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0205 g, 31.3%): TOF MS ESt 358.2 (M+H)+, HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2131 time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.8 min, 100% purity.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1>>[NH:22]([C:19]1[S:20][CH:21]=[C:17]([CH2:16][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)[N:18]=1)[C:23]([NH2:25])=[NH:24]
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] is reacted with 4-chloromethyl-2-guanidinothiazole hydrochloride and a strong base, the title compound is thereby produced, which is identical to the product obtained in Example 31.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[I-:10].[Na+].C(Cl)(=O)C>C(#N)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([I:10])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1cc(I)ncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile (40 ml) at room temperature under argon were added sodium iodide (4.8 g) then acetyl chloride (0.94 g). After 3 hours stirring at room temperature the white solid formed was filtered off and the filtrate was neutralized with aqueous saturated solution of sodium hydrogenocarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/cyclohexane) to afford the title product as a brown solid (2.04 g). 1H-NMR (CDCl3, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s, 3H),
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:18][CH2:17]1.[O:32]=[C:33]1[NH:41][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]1[CH:42]1[CH2:47][CH2:46][N:45](C(Cl)=O)[CH2:44][CH2:43]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25]([N:45]2[CH2:44][CH2:43][CH:42]([N:34]3[C:35]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[NH:41][C:33]3=[O:32])[CH2:47][CH2:46]2)=[O:31])[CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Triethylamine (0.45 mL, 3.25 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (416 mg, 1.62 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (466 mg, 1.66 mmol) in dichloromethane (70 mL) and the mixture heated to reflux. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane o 95% dichloromethane/methanol) gave the title compound (685 mg). MS 501.0 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]CC)=[O:10].Cl>O>[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1nc[nH]c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cnc1C(=O)O

Procedure:
Sodium hydroxide (70.0 g, 1.75 moles), followed by ethyl 5-methyl-1H-imidazole-4-carboxylate (34.0 g, 0.22 mole), were added to 500 ml of water. The reaction mixture was stirred and heated at reflux for one hour, cooled in an ice bath, and neutralized with 150 ml of concentrated hydrochloric acid. The precipitated solid was collected and dried to give 5-methyl-1H-imidazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:16]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:16])=[O:4]
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Yield: 83 %

Procedure:
2-Amino-3-(4-nitrophenyl)propionic acid (4.60 g, 21.9 mmol) was added to a mixed solution of methanol (100 ml) and chloroform (50 ml), and sulfuric acid (3 ml) was added, which was followed by refluxing under heating for 30 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The pH was adjusted to 8-9 with a 1N aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 4.06 g of methyl 2-amino-3-(4-nitrophenyl)propionate as a yellow oil (83%). This oil (4.00 g, 17.8 mmol) was dissolved in acetonitrile (56 ml), and pyridine (1.76 ml, 21.4 mmol) and n-butylsulfonyl chloride (2.80 g, 17.8 mmol) were sequentially added, which was followed by stirring at 70° C. for 4.5 hours. After cooling, the reaction mixture was poured into water (70 ml) and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 4.06 g of methyl 2-(n-butylsulfonylamino)-3-(4-nitrophenyl)propionate as an orange oil (66%). This oil (3.40 g, 9.88 mmol) was dissolved in acetic acid (130 ml) and 10% palladium-carbon (1.5 g) was added. The mixture was stirred for 3 days under a hydrogen atmosphere. The reaction mixture was filtered through Celite and acetic acid was distilled away from the filtrate under reduced pressure to quantitatively give 3.16 g of methyl 3-(4-aminophenyl)-2-(n-butylsulfonylamino)propionate as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([CH3:22])[C:17](=O)[CH2:18][CH:19]=O>>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH:16]([CH3:22])[CH3:15])[CH:18]=[CH:19][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)CC=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Product: CC(C)c1ccn2nc(SCc3ccccc3)nc2n1
Yield: 96 %

Procedure:
This material was prepared in 96% yield from 3-amino-5-benzylthio-1,2,4-triazole and 4-methyl-3-oxopentanal following the general procedure described in Example 7. The desired product was isolated as a solid, m.p. 65°-66° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](O)=[O:25])=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:14]([F:27])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:42]C=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]([C:23]1[CH:22]=[N:21][CH:20]=[CH:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:13][C:14]=1[F:27])(=[O:25])[NH2:42]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(N)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
(S)-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinic acid (75 mg, 0.173 mmol) was taken in DMF (2 mL) and cooled to 0° C. To the solution was added EDC (49.9 mg, 0.260 mmol) and HOBT (53.1 mg, 0.347 mmol). After stirring the reaction mixture for 5 min, ammonium chloride (55.7 mg, 1.040 mmol) was added and the resultant mixture was stirred for 5 min. Diisopropylethylamine (0.121 mL, 0.694 mmol) was added and the mixture was allowed to stir at room temperature for an additional 12 h. The mixture was then quenched with ice and the residue was filtered and dried under vacuum to afford (S)-tert-butyl (1-(4-(3-carbamoylpyridin-4-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.098 mmol, 57% yield) as a light yellow solid. LC/MS (ESI) m/e 432.2 [(M+H)+, calcd for C23H31FN3O4 432.2]; LC/MS retention time (method C): tR=1.83 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:21][C:20]=1[CH3:33]>N1C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:19]([NH:18][C:9](=[O:11])[CH:8]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=3)=[C:20]([CH3:33])[N:21]=2)=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(N)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Nc2sc(-c3ccc(Cl)cc3OC)nc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
4-Methoxycinnamic acid (178 mg, 1.0 mmol) and thionyl chloride (480 mg, 4.0 mmol) were heated under reflux for 2 hours. The excess thionyl chloride was distilled off. The resulting residue was dissolved in pyridine (1 ml). Under an ice cooling, the resulting solution was added to a solution of 5-amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole (254 mg, 1.0 mmol) prepared in the Step 28-1-2 in pyridine (4 ml). After the removal of the ice bath, the mixture was stirred for 16 hours at a room temperature. To the mixture, 3.5% hydrochloric acid was added, and the resulting mixture was subjected to extraction with chloroform. The extract was washed with water. The washed product was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (54 mg, 13%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:18])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:18])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Br[Mg]c1ccccc1
Reactant: COCNC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylic acid t-butyl ester (400 mg, 1.6 mmol) and THF (10 mL, 0.1 mol) were combined under nitrogen. The solution was cooled at 0° C. using an ice bath. 1.0 M of Phenylmagnesium bromide in THF (7.0 mL, 7.0 mmol) was added dropwise over 5 minutes. The mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice bath and the reaction was quenched by the slow addition of water (15 mL). The mixture was extracted with EtOAc (1×100 mL), and the organic layer was washed with sat. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated to yield 849 mg of crude product, which was purified by flash chromatography (12 g column, 20-100% EtOAc in hexanes over 17 minutes), and placed under high vacuum for 15 minutes to yield 372 mg of the title compound as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(C)C=CC=C[C:19]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C(C([SnH3])=C(CCCC)CCCC)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[CH:18]([C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1)=[CH2:19]
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: CCCCC([SnH3])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=Cc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Yield: 186.9 %

Procedure:
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (150 mg, 0.508 mmol), tris(dibenzylidineacetone)dipalladium (0) (22 mg, 0.024 mmol), tri(o-tolyl)phosphine (63 mg, 0.206 mmol), lithium chloride (103 mg, 2.43 mmol), and tri-n-butylvinylstannane (188 mg, 0.592 mmol) in 1,2-dimethoxyethane (10 ml) was heated under reflux overnight. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-25% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (93 mg, 0.385 mmol, 76%) as a pale solid: electrospray MS (m/z, relative intensity) 243 ([MH]+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>CO.O1CCCC1>[CH:18]1([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn(-c2ccc(C3CC3)cn2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cnn1-c1ccc(C2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 1-(5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (14 g) in methanol (70 ml) and tetrahydrofuran (70 ml) were added 4 N aqueous solution of sodium hydroxide (70 ml) and water (50 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (12.4 g) as a white solid. MS (ESI) m/z: 244 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:18]=2)=[C:13]([F:30])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:18]=2)=[C:13]([F:30])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a stirred solution of intermediate ethyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (270 mg, 0.65 mmol, 1.0 eq) in THF (4 mL) was added NaOH (2 M aqueous solution, 2.5 mL, 5 mmol, 7.7 eq). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude material obtained was crystallised from CH2Cl2/petroleum ether, collected by filtration and dried in vacuo to give the title compound (I(e)) as a white solid (190 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[C:3](I)=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:17]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[OH:1][C:2]1[C:3]([CH3:17])=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)/C=C/c1ccc(OC)c(O)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CO
Product: COC(=O)/C=C/c1ccc(OC)c(O)c1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2E)-3-(3-hydroxy-2-iodo-4-methoxyphenyl)prop-2-enoate (2.0 g, 5.99 mmol) in methanol (30 ml) was added trimethylboroxine (1.683 ml, 11.97 mmol), potassium carbonate (2.482 g, 17.96 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.170 g, 1.796 mmol). The mixture was stirred overnight at 90° C. The solution was then filtered through a plug of silica gel (eluting with ethyl acetate), concentrated in vacuo and the residue was purified via column chromatography on a Biotage 65i column eluting with hexanes (1 CV) followed by a gradient of 0-50% ethyl acetate in hexanes (over 6.7 CVs) to furnish the desired compound. 1H NMR (CDCl3, 500 MHz) δ 7.95 (d, J=15.9 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.27 (d, J=15.8 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.34 (s, 3H).