Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]1([CH:13]=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][CH2:13][CH:10]2[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=CC1CC1
Reactant: Cc1nc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc(Cl)ccc1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a dry flask, 6-chloro-2-methylpyridin-3-amine (200 mg, 1.40 mmol) and cyclopropanecarbaldehyde (116 μl, 1.54 mmol) were taken up in 1,2-dichloroethane (5.6 ml) under argon. The resulting clear solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.47 g, 2.10 mmol) and acetic acid (160 μl, 2.81 mmol) were sequentially added to the reaction mixture, which was stirred as such for 24 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted three times with dichloromethane. All organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:7][C:6]=2[C:5](=O)[NH:4][N:3]=1.O=P(Cl)(Cl)[Cl:18].CO.[OH-].[Na+]>C(Cl)Cl>[Cl:18][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: Cc1n[nH]c(=O)c2cc3n(c12)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Yield: 92 %

Procedure:
Compound XI (3.00 g, 15 mmol) was heated under reflux with excess POCl3 (25 mL) until no starting material remained (TLC, silic gel, 5% methanol in methylene chloride), then poured over ice, made basic with aqueous sodium hydroxide and the aqueous phase extracted with methylene chloride to isolate the product. The organic phase was dried (MgSO4), filtered, and evaporated to give a residue which was purified by flash column chromatography (silica gel, 5% methanol in methylene chloride) to give 1-chloro-4-methyl-6,7,8,9-tetrahydropyridazino[4,5-b]indolizine XII (3.00 g, 92%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[NH3:11]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH2:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: N
Solvent: CO
Product: COc1cnc(Cl)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4 dichloro-5-methoxypyrimidine (0.45 g, 2.5 mmol) and ammonia in methanol (2N, 20 ml) was stirred at room temperature overnight. The mixture was then concentrated in vacuo and washed with water. The residue was purified by column chromatography (20-60% ethyl acetate/petroleum ether) to furnish the title compound as a white solid (211 mg). MS: [M+H]+=160
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CCOC(C)=O.CO>[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH:27]=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=Cc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A solution of ethyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-1,3-oxazole-4-carboxylate (preparation 155) (1.50 g, 3.39 mmol) in toluene (50 ml) at −78° C. was treated dropwise with DIBAL (1M in hexanes) (11.86 ml, 11.86 mmol) and stirred at this temperature for 30 minutes. MeOH (12 ml) was added to quench the reaction and the reaction mixture allowed to warm to room temperature. Alternate portions of NaHCO3 and MgSO4 were added to the reaction mixture to form a white paste. EtOAc was added and the solid filtered off. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (1:1) gradually changing to (1:0) to afford the title compound as a colourless oil (605 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:26][N:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1CN1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(CN3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.26 g) and 5-amino-2-((4-morpholinopiperidin-1-yl)methyl)benzonitrile (0.3 g), the title compound (0.16 g) was obtained, melting point: 167–168° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (91 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide (106 mg, 58%) as a white foam: mp 92-95° C. (foam to gel); FAB-HRMS m/e calcd for C20H23N3O5S (M+H)+ 418.1436, found 418.1430.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCc1ccsc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3ccccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.2 g (0.73 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.64 mL (0.95 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.27 g (100% of yield) of 4-(1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1sc(SCc2ccccc2)nc1C

Procedure:
2.03 g (0.01 mole) of methyl 2-mercapto-4-methyl-1,3thiazol-5-ylacetate are reacted with potassium carbonate and benzyl chloride in acetone and worked up in accordance with Example 1, stage 2.
Reaction SMILES: S1C=CC=C1CC([O-])=O.[K+].[Cl:11][C:12]1[C:17]([Cl:18])=[C:16]([O:19]C)[CH:15]=[CH:14][C:13]=1[C:21]([C:23]1[N:27]([CH2:28][O:29][CH2:30][CH3:31])[N:26]=[CH:25][CH:24]=1)=[O:22].O.C(O)(=O)C>CS(C)=O>[Cl:18][C:17]1[C:12]([Cl:11])=[C:13]([C:21]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH3:31])[N:26]=[CH:25][CH:24]=2)=[O:22])[CH:14]=[CH:15][C:16]=1[OH:19]
Reactant: CCOCn1nccc1C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: O=C([O-])Cc1cccs1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOCn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Reaction time: 4 h
Yield: 71.3 %

Procedure:
9.45 g of potassium thiolacetate are added to a solution of 5.45 g of (2,3-dichloro-4-methoxyphenyl)(1-ethoxymethyl-5-pyrazolyl)methanone in dimethylsulfoxide and the mixture is stirred at 90°-100° C. under argon gas atmosphere for 4 hours. After cooling the solution, cold water is added thereto, and the mixture is adjusted to pH 5-6 with acetic acid and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 3.72 g of 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH-:5].[Na+:6].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1>[Cl-].[Na+].O.ClCCl>[CH3:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1)([C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH3:15].[C:1]([OH:2])([OH:7])=[O:5].[Cl-:3].[Na+:6]
Reactant: [OH-]
Reactant: O=C(Cl)Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)O

Procedure:
The manufacture of condensation polymers often produces a brine solution as a by-product. For example, a brine solution is produced in the manufacture of polycarbonate resins through the reaction of phosgene with at least one bisphenol compound in an organic solvent in the presence of aqueous sodium hydroxide. A common example is the reaction of bisphenol A with phosgene in dichloromethane in the presence of aqueous sodium hydroxide to produce bisphenol A polycarbonate and sodium chloride solution.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([O:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[C@H:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5]1)(=O)[CH3:2].CO.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C1COCC1.B>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[F:25][C:22]([F:23])([F:24])[C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:11][O:10][C@H:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH3:2])[CH2:5][C@H:6]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Agent: B
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of the compound (0.88 g) obtained in Example 2 in THF (10 ml), 1 M borane and THF complex (10 ml) was added at 0° C., and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled, and then methanol (2 ml) was added thereto, and concentrated under reduced pressure. To the obtained residue, 6 N hydrogen chloride (6 ml) and methanol (6 ml) were added, and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled, and then made basic with an aqueous 12 N sodium hydroxide solution. The mixture was concentrated under reduced pressure, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (acetone:methanol=20:1), and treated with 1 equivalent of oxalic acid to obtain the title compound as colorless crystals (0.52 g, 61%).
Reaction SMILES: COC1C(C=O)=CC2N(C)C(=O)CCC=2N=1.[CH2:17]([CH:19]1[NH:24][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]([NH:31][CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[N:35][C:34]=2[O:45][CH3:46])[CH2:21][CH2:20]1)[CH3:18]>CCCCCCC.C(O)C>[CH2:17]([C@@H:19]1[NH:24][C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:22]([NH:31][CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[N:35][C:34]=2[O:45][CH3:46])[CH2:21][CH2:20]1)[CH3:18]
Reactant: CCC1CCC(NCc2cc3c(nc2OC)CCC(=O)N3C)C(c2ccccc2)N1
Agent: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Solvent: CCCCCCC
Solvent: CCO
Product: CC[C@H]1CC[C@H](NCc2cc3c(nc2OC)CCC(=O)N3C)[C@H](c2ccccc2)N1

Procedure:
By a procedure similar to the previous example 74: starting with cis-2-phenyl-3-amino-trans-6-ethyl-piperidine (scheme J) and 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde (Example 74, step 5) and using the above coupling procedure (Example 74, step 6) 7-[(6-ethyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one was obtained. Using a CHIRALPAK AD (10×50 cm) and a mobil phase of 95:5 heptane/ethanol containing 0.025% diethyl amine (flow rate=275 ml/min) 7-[(6(S)-ethyl-2(S)-phenyl-piperidin-3(S)-ylamino)-methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (retention time 13.545 min) was isolated as a pure enantiomer. 1H NMR (CDCl3) δ 7.40 (m, 2H), 7.35 (m, 2H), 7.2 (m, 1H), 4.20 (s, 1H), 3.75 (s, 3H), 2.82, 2.42 (d,d, 2H), 3.17 (s, 3H), 3.08 (m, 1H), 2.90 (m, 2H), 2.85 (m, 1H), 2.65 (m, 2H), 1.8–2.2 (m, 6H), 1.7 (m, 1H), 1.55 (m, 1H), 1.38 (m, 1H), 0.9 (t, 3H). Mass spectrum: m/e=409.2 (p+1). The corresponding 7-[(6(R)-ethyl-2(R)-phenyl-piperidin-3(R)-ylamino)-methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one enantiomer (retenton time 14.539 min) was also isolated. NMR and mass spectrum was identical to the above spectra.
Reaction SMILES: [N:1]1([CH2:8][C:9]2[S:13][C:12]([C:14](=[N:16][OH:17])[NH2:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:21](=O)[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C>>[C:27]([O:26][C:24]([NH:23][CH2:22][C:21]1[O:17][N:16]=[C:14]([C:12]2[S:13][C:9]([CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[N:15]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: NC(=NO)c1ccc(CN2CCCCCC2)s1
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCc1nc(-c2ccc(CN3CCCCCC3)s2)no1
Yield: 41.8 %

Procedure:
Using 1.7 g of 5-(hexahydro-1H-azepin-1-yl)methyl-2-thiopheneamidoxime and 2.0 g of N-t-butoxycarbonylglycine ethyl ester, 1.1 g of the title compound was obtained in the same manner as described in the step 1) of Example 56.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:13]2)=[C:4]([F:29])[CH:3]=1.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([C:20]([F:21])([F:23])[F:22])[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:13]2)=[C:4]([F:29])[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c(C)c1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1nn(-c2cc(O)c(Cl)cc2F)c(=O)c(C)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
One gram (1.0 g) of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-ethoxycarbonyl-4-methyl-5-trifluoromethylpyridazin-3-one and 1.0 g of sulfuric acid are mixed at room temperature, and stirred for 30 minutes. The reaction mixture was poured into water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of water 3 times and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained crystals was washed with 50 ml of n-hexane to afford 0.78 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-ethoxycarbonyl-4-methyl-5-trifluoromethylpyridazin-3-one, the present compound 1-27 (yield 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[CH:18](C1C=CC=CC=1C)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:18])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: Cc1ccccc1C(N)C(=O)O
Product: COC(=O)NC(C(=O)O)c1ccccc1C

Procedure:
Methoxycarbonylamino-o-tolyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-o-tolyl-acetic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.94 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35].C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[N:16]2[CH2:33][C:34]([OH:36])=[O:35])=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(c1)NC(=O)CC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(c1)N(CC(=O)O)C(=O)CC2
Temperature: 57 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
A solution of 7-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3,4-dihydro-1H-quinolin-2-one (233 mg, 0.557 mmol) in DMF (3.0 mL) is treated with NaH (67 mg, 1.67 mmol, 60%). The resulting suspension is heated at 57° C. for 40 minutes and cooled to room temperature. The t-butyl bromoacetate (217 mg, 1.11 mmol) is added and the suspension is stirred for 2 hours and then quenched with water. The mixture is extracted with EtOAc (30 mL×2) and the combined organics are dried (Na2SO4), concentrated, and purified on silica gel chromatography column with 20% EtOAc/Hexanes to obtain the intermediate compound. The intermediate is then treated with TFA (1.0 ml), CH2Cl2 (1.0 ml), H2O (0.1 mL) and stirred for 2 hours, concentrated and purified on silica gel chromatography (Hexanes/EtOAc/HOAc, 5/5/0.02) afford the title compound (65 mg, 25%). MS (MH+): 477.1; the structure is also confirmed by proton NMR.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=CC=CC=1C(Cl)=O)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 92 %

Procedure:
The compound of example 151 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-phenoxy benzoyl chloride.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14](=[O:24])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH2:10]2)=O)C.C[Si](I)(C)C.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:14]([CH:9]1[CH2:10][CH:11]2[NH:6][CH:7]([CH2:13][CH2:12]2)[CH2:8]1)=[O:24]
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)NCc1ccccc1F)C2
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1F)C1CC2CCC(C1)N2
Yield: 76.5 %

Procedure:
A solution of 0.15 g of 3-(2-fluoro-benzylcarbamoyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester and 0.5 mL of trimethylsilyl iodide in 25 mL of chloroform was kept at room temperature for 48 h, shaken with 25 mL of 6N NaOH and dilute sodium sulfite and dried over magnesium sulfate. Removal of solvents gave 0.09 g of a resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([C:8]#[C:9][C:10]([O:12]C)=[O:11])=[O:7].[OH-].[K+].O>O1CCCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:16]=1[O:17][CH3:18])[C:6]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: COC(=O)C#CC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)C#CC(=O)O)cc(OC)c1OC
Reaction time: 1.5 h

Procedure:
A solution of 2.8 g (10 mmol) of methyl 3-(3,4,5-trimethoxybenzoyl)propiolate in 30 ml of tetrahydrofuran was treated slowly at 0° with 28 ml of 3% potassium hydroxide solution and subsequently stirred at 0° for a further 1.5 hours. The reaction mixture was treated with water and extracted once with ether. The ether phase was discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and evaporated. Crystallization of the residue from methylene chloride/ether/hexane yielded 3-(3,4,5-trimethoxybenzoyl)-propiolic acid of melting point 130°-132°.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[NH2:12].O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:20])([F:21])[F:19]
Reactant: CC1(C(=O)O)CC1
Reactant: Nc1ccc(OCC(F)(F)F)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C(=O)Nc2ccc(OCC(F)(F)F)c(Cl)c2)CC1
Yield: 82.9 %

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (1.8 g) in pyridine (50 ml), a solution of 3-chloro-4-(2,2,2-trifluoroethoxy)aniline (2.3 g) in pyridine (10 ml) cooled with ice was dropwise added while stirring. After stirring at room temperature for 10 hours, the reaction mixture was admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.8 g) were recrystallized from ethanol to give N-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-1-methylcyclopropanecarboxamide (2.6 g). M.P., 95°-96° C.