Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:10][C:11](=[O:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:13]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.Cl>CO>[CH2:27]([O:26][C:13]1[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:12]=1[C:11]([OH:34])=[O:10])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 65 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
NaOH (1 N) (150 mL) was added to compound 36 (4.3 g) in MeOH (50 mL). The reaction mixture was heated to 65° C. with stirring for 48 h. After the reaction mixture was cooled down to room temperature, 1.0 M HCl (200 mL) was added to neutralize the reaction mixture. The solvent was concentrated under reduced pressure. The residue was extracted with CHCl3 and H2O. The combined organic layer was dried over MgSO4. After the MgSO4 was filtered off, the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give the compound 37 (1.3 g) as a solid with total yield of 38.92% for 2 steps. LC-MS (ESI): m/e=335.2 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:35][C:34](=[O:44])[CH:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[NH:35][C:34](=[O:44])[CH:33]=4)=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 84 mg (purity 90%, 0.28 mmol, 1.1 eq.) of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 17 mg (purity 70%, 8% of theory)
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH2:4]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCC[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCC[C@@H](CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.5 %

Procedure:
Benzyl 4-{[(3R)-1-ethylpiperidin-3-yl]methyl}piperazine-1-carboxylate (352 mg) was dissolved in ethanol (50 ml). 10% Palladium on carbon (35 mg) was added and the mixture stirred for 18 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound (225 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:13](N(OC)C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH:26]([Mg]Br)=[CH2:27].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:13](=[O:14])[CH:26]=[CH2:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 2-[3-chloro-4-(methylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (8.64 g) in tetrahydrofuran (90 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 88.8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hr, and added to 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (7.15 g, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]O)=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][O:14][C:10]2[C:11]([CH3:13])=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][C:9]=2[CH3:15])=[CH:20][N:19]=1
Reactant: COc1ccc(CCCO)cn1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)cn1
Yield: 72.6 %

Procedure:
To a suspension of 0.81 g (3.9 mmol) of 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.8 g (1.2 eq) of 2-methoxy-5-(3-hydroxypropyl)-pyridine, 1.4 g (1.2 eq) of triphenylphosphine in 70 ml of methylene chloride under nitrogen at 5° C. was added in portions 0.88 g (1.2 eq) of DEAD. The mixture was concentrated in vacuo, the residue was triturated with ether, filtered, and the crude product was purified by MPLC (50 id,Kieselgel 60 column, hexane/ethyl acetate, 2:1) and recrystallization from isopropyl acetate/hexane to afford 1 g (71.4%) of 2-methoxy-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a white powder, m.p. 71°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[C:24]([CH3:25])=[CH:23][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][C:9]=2[CH3:26])=[O:7])=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([CH3:26])=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])=[CH:23][C:24]=2[CH3:25])=[O:7])=[CH:27][CH:28]=1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(C(=O)c2ccc(Cl)cc2)c(C)c1
Solvent: CO
Product: Cc1cc(OCCCC(C)(C)C(=O)O)cc(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
The ester of Example 3 is saponified with methanol containing soda to give the desired acid, m.pt 135° C.
Reaction SMILES: [CH:1]1([C:6]2([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C:6]2([CH3:12])[C:7](=[O:11])[CH:8]=[CH:9][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C2CCCC2)CCCC1=O
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C2CCCC2)CC=CC1=O

Procedure:
Four grams (0.026 mole) of 2-cyclopentyl-2-methyl-cyclopentanone dissolved in 20 ml. of chloroform is cooled to 0°C. and 4.2 g. (0.026 mole) of bromine is added over a 40 minute interval. An aqueous 5 wt. % solution of sodium bisulfite is added to destroy the excess bromine followed by 10 wt. % aqueous sodium hydroxide solution to achieve a pH of 7. The aqueous layer is discarded after back extraction with 20 ml. of chloroform. After washing the combined chloroform layers with water and drying over magnesium sulfate, the chloroform is removed at reduced pressure. Pyridine, 20 ml., is added and the solution is refluxed for one hour, cooled and diluted with 100 ml. water. 100 Ml. of chloroform is added and the layers are separated. The chloroform layer is washed with 50 ml. of 6 molar HCl and then dried over magnesium sulfate. Evaporation gives 5-cyclopentyl-5-methyl-2-cyclopentenone suitable for use in the Diels-Alder reaction of Step 1.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]1[C:48](=[O:49])[N:47]2[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:46]2[C:45](=[O:54])[NH:44][CH2:43]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:48](=[O:49])[N:47]2[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:46]2[C:45](=[O:54])[NH:44][CH2:43]1)=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3CNC(=O)[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((4R,10aR)-1,5-dioxodecahydropyrido[1,2-a][1,4]diazepin-4-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (20 mg, 0.035 mmol) and Intermediate 39 (7.0 mg, 0.035 mmol) to give a white solid (15 mg, 56% yield). Anal. Calcd. for C40H51N5O7S m/z 745.7. found: 746.5 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.70 (m, 3H), 7.29-7.02 (m, 7H), 5.67-5.52 (m, 1H), 5.09-4.91 (m, 2H), 4.36 (d, J=13.0 Hz, 1H), 3.83-3.75 (m, 1H), 3.73-3.64 (m, 1H), 3.64-3.52 (m, 4H), 3.22-2.98 (m, 2H), 2.82-2.61 (m, 4H), 2.60-2.34 (m, 8H), 2.18 (d, J=13.8 Hz, 1H), 2.09-1.88 (m, 2H), 1.86-1.73 (m, 2H), 1.71-1.15 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of 3,4-dihydroxybenzonitrile (540 mg, 4 mmol), K2CO3 (552 mg, 4 mmol) and benzyl bromide (476 mg, 4 mmol) in acetone (20 mL) was stirred at room temperature for 3 days. The mixture was evaporated under vacuum and subjected to flash column chromatography (2% MeOH in toluene-hexane, 2:1) to give the desired product (224 mg, 25%): MP 101° C.; 1H NMR (Acetone-d6, 500 MHz) δ 8.55 (s, 1H), 7.50 (d, 2H, J=7.3 Hz), 7.39 (dd, 2H, J=7.0 and 7.3), 7.34 (dd, 1H, J=7.0 and 7.3), 7.2 (m, complex, 3H). 5.25 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
1: Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0° C. and treat with Cs2 CO3 (100 g, 307 mmol, 0.66 eq). Stir the resulting off-white slurry for 15 min, then add CH3I (33 mL, 530 mmol, 1.15 eq) via syringe. After 1 h, add additional DMF (250 mL), stir the slurry for 14 h and partition between EtOAc (1.5 L) and half saturated aqueous NaHCO3 (500 mL). Separate the organic layer and extract the aqueous layer twice with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHCO3 (500 mL) and water (5×500 mL), then dry (Na2SO4) and concentrate to obtain 105.4 g (456 mmol, 99%) of methyl 3-(3,4-dichlorophenyl)-2-propenoate as light brown needles.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH3:19])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9])=C.Cl.C(=O)([O-])O.[Na+]>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH3:19])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.2 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (64 mg, 0.13 mmol), 1N aqueous HCl (0.39 mL) and MeOH (4.0 ml) was stirred at room temperature for 20 hours. Sodium hydrogen carbonate (32 mg, 0.39 mmol) was added, stirring was continued for 10 minutes then the reaction mixture was concentrated under reduced pressure. The residue was absorbed onto HM-N and purified by flash chromatography (Si-PPC, dichloromethane:MeOH, gradient 100:0 to 85:15) followed by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl, 0.1% TFA in water on a gradient of acetonitrile 95:5 to 50:50) to afford the title compound as a yellow solid (16 mg, 27%). LCMS (method A): RT=5.75 min, M+H+=471. 1H NMR (d4-MeOH, 400 MHz) 8.55 (s, 1H), 8.24 (d, J=6.2 Hz, 1H), 7.52 (d, J=6.2 Hz, 1H), 7.39 (dd, J=10.8 Hz, 1.8 Hz, 1H), 7.14-7.19 (m, 1H), 6.35 (dd, J=8.7 Hz, 8.7 Hz, 1H), 3.94 (s, 3H), 3.88 (t, J=4.5 Hz, 2H), 3.64 (t, J=4.5 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:25])=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH:17]=3)=[N:9][N:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:25])=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH:17]=3)=[N:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C)CC4)o3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-piperidin-4-yl-[1,3,4]oxadiazol-2-yl)-5-p-tolyl-pyridin-2-ylamine (250 mg, 0.746 mmol) in THF (25 mL) was added NaH (55%) (48.8 mg, 1.119 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then MeI (95 mg, 0.671 mmol) was added at 0° C., and the reaction mixture was stirred at 0° C. for a further 3 h. The reaction mixture was then poured into ice-water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. Crude compound was purified by preparative HPLC to afford the title compound as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[S:27][C:26](=[O:29])[NH:25][C:24]=3[CH:23]=[C:22]([Br:30])[CH:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-].Cl>O1CCOCC1.O>[Br:30][C:22]1[CH:21]=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C@@H:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])[C:28]2[S:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=1
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Reaction time: 1 h
Yield: 34 %

Procedure:
(S)-3-[3-(5-Bromo-2-oxo-2,3-dihydro-benzothiazol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (33 mg, 0.06 mmol) is dissolved in dioxane (3 mL) and then LiOH (8 mg, 0.3 mmol) in water (3 mL) is added to the reaction. The reaction is stirred for 1 hour then acidified with 4N HCl and the solvents evaporated in vacuo. The resulting crude solid is purified on reverse phase LC/MS to give 10 mg (32%) of the title compound as a white solid. LCMS (ESMS): m/z 491.8 (M+H+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]21[O:4][CH2:1][CH2:2][O:3]2)=[O:20])[CH3:17]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCCCC12OCCO2
Temperature: 25 °C
Yield: 74 %

Procedure:
Under an argon atmosphere, ethylene glycol (7.6 ml, 135.87 mmol) and para-toluenesulfonic acid (516 mg, 2.72 mmol) were added to a solution of (±)-2-(ethoxycarbonylmethyl)cyclohexanone (5.00 g, 27.17 mmol) in toluene (136 ml). The mixture was heated to reflux in a Dean Stark apparatus for 4 h and then allowed to cool to room temperature and quenched with sodium bicarbonate (5 g) and a saturated sodium bicarbonate solution (150 ml). The organic phase was separated from the aqueous phase which was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with a saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (9:1) to give (±)-6-(ethoxycarbonylmethyl)-1,4-dioxaspiro[4.5]decane (4.59 g, 74% yield) as a colourless oil. Rf 0.18 (hexane-ethyl acetate, 9:1).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[S:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=2[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1>O1CCOCC1>[Br:3][C:4]1[C:12]2[S:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=2[CH:7]=[C:6]([C:17]([F:20])([F:18])[F:19])[CH:5]=1
Reactant: COC(=O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Temperature: 70 °C

Procedure:
A solution of NaOH (4.0 M in water, 5.0 mL, 20 mmol) was added to a solution of methyl 7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylate (1.00 g, 2.95 mmol) in dioxane (11 mL). The mixture was heated at 70° C. overnight, allowed to cool to room temperature, then concentrated. The resulting light beige solid was partitioned between water (25 mL) and 1:1 hexanes:ethyl acetate (15 mL). The resulting layers were separated. The aqueous layer was adjusted to pH 2 with 2.0 M HCl (aq) then extracted four times with CH2Cl2. The combined CH2Cl2 layers were dried over Na2SO4, filtered, then concentrated. The resulting acid, a light yellow solid, was used directly for the following step. LC1: 3.58 min. Compound does not ionize.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
100 mg of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (produced in Intermediate Production Example 1) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 42 mg of anhydrous potassium carbonate, and 46 mg of ethyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 2 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 85 mg of ethyl 2-[4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 1-2 of the present invention].
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:13][C:12]([SH:14])=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:8][C:9]1[S:13][C:12]([S:14][C:18]2[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=2)=[N:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Sc1nnc(SCc2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Sc1nnc(SCc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(benzylthio)-1,3,4-thiadiazole-2-thiol (240 mg, 1.00 mmol) in DMF and benzene (4 ml, 1/1) was added NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol) slowly at 0° C. under a nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4. Removal of the solvent gave the crude product which was purified by chromatography to give the title compound as off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(C1C=[C:30](C(=O)C2C=CC(C)=CC=2)[N:31]2C3C(=CC=CC=3)C=C[C:32]=12)#N>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:31]([CH3:32])[CH3:30])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: Cc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Reactant: N#Cc1cc(C(=O)c2ccc(CBr)cc2)n2c1ccc1ccccc12
Product: CN(C)Cc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
3-Cyano-1-[4-(bromomethyl)benzoyl]-pyrrolo[1,2-a]quinoline. The title compound was prepared similar as Example 53a, using 3-cyano-1-(4-methylbenzoyl)-pyrrolo[1,2-a]quinoline to yield 230 mg (68%). 1H NMR (CDCl3): 8.09–8.10 (m, 3H), 7.87–7.52 (m, 7H), 7.43 (s, 1H), 4.58 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]([Cl:17])([Cl:16])[C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:14]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 86.8 %

Procedure:
To a solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole in 200 milliliters xylene at 110° C. was added 18.2 grams (0.1 mole) trichloroacetyl chloride over 0.5 hour. After heating for an additional 20 hours at 120° C., the low boiling materials were distilled in vacuo to leave 15.8 grams (87% yield) of pure product as residue; m.p. 157.7° C.