Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]([S:19](Cl)(=[O:21])=[O:20])([CH3:18])[CH3:17]>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1
Temperature: 70 °C
Yield: 2.2 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.27 g, 1.37 mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol) and heated to 70° C. for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propane-2-sulfonamide (0.009 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12(C(OCC)=O)CC(C=C1)[CH:20]1[CH:16]2[CH:17]=[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]1>O1CCOCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([C:18]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH:20]2[CH:16]=[CH:17]3)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CCOC(=O)C1=CC2C(C1)C1C=CC2(C(=O)OCC)C1
Solvent: C1COCCO1
Product: CCOC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12

Procedure:
32.8 g (0.17 mol) of N-benzylmaleimide are heated under reflux with 24.2 g (0.17 mol) of diethyl tricyclo[5.2.1.02,6 ]deca-3,8-diene-1,4-dicarboxylate in 200 ml of 1,4-dioxane overnight. The mixture is concentrated, the residue is taken up in 80 ml of isopropanol and the product is allowed to crystallize out.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[C:36](O)=[O:37]>O>[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[C:36]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:15]1[S:14][C:11]2[C:10]([N:16]=1)=[CH:9][C:8]([CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH:13][N:12]=2)=[O:37]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C28H25N5O3S: 511.17. Found (M+H)+ m/z=512.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6]C[CH2:4]2.C([OH:13])C>[Pd]>[NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6][O:13][CH2:4]2
Reactant: CCO
Reactant: NCC12CCCC1CNC2
Agent: [Pd]
Product: NCC12CNCC1COC2

Procedure:
2.8 g (12.1 mmol) of 1-aminomethyl-7-azabicyclo[3.3.0]octane are dissolved in 50 ml of ethanol and hydrogenated on 0.3 g of palladium-active charcoal at 100° C. and 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated and distilled. Yield: 1.5 g (87% of theory) Boiling point: 70°-72° C./0.03 mbar.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:43][O:44]C)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[I:49]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:31]([I:49])=[C:32]([CH:33]2[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]2)[O:44][N:43]=1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)CC1CC(C#CC(=NOC)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 4.5 h
Yield: 80.4 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-[3-(2-ethylbutyl)cyclobutyl]-4-methoxyimino-5-hexynoate (7.50 g) and acetonitrile (60 mL) were mixed. To the mixture was added iodine (7.54 g) was added at ice temperature. The mixture was stirred for 4.5 hr, and then to the mixture were added aqueous 5 w/v % sodium thiosulfate (50 mL), ethyl acetate (200 mL) and aqueous 5 w/v % sodium thiosulfate (75 mL, 150 mL) at ice temperature. The aqueous layer was removed, and the organic layer was washed with saturated aqueous sodium bicarbonate/brine=1/1 (100 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified twice by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/50→1/40→1/20) to give the title compound (7.1 g).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[S:15][C:14](/[CH:16]=[CH:23]/[N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cc2ccc(C=O)s2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To an acetic acid (10.0 mL) solution of 5-(4-methyl-benzyl)-thiophene-2-carbaldehyde (1.05 g, 4.85 mmol) described in Manufacturing Example 91-1-2 were added nitromethane (1.48 g, 24.3 mmol) and ammonium acetate (748 mg, 9.70 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.20 g) as a crude product.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>CN(C)C=O.COC(OC)OC.Cl>[CH3:17][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: C=O
Agent: Cl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCC(C#N)(c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4-Phenylpiperidine-4-carbonitrile (1.35 g, 6.062 mmol) was dissolved in N,N-dimethylformamide/trimethylorthoformate (1:1, 12 mL) and treated with paraformaldehyde (0.596 mL, 18.19 mmol), triacetoxyborohydride (3.854 g, 18.185 mmol) and acetic acid (1 mL). The mixture was stirred at 23° C. overnight, then diluted with 1N hydrochloric acid and washed with ethyl acetate. The aqueous phase was basified with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (1.05 g, 50%) as an oil. LC/MS (M+H)+: 200. HPLC ret. time (Condition B): 1.315 min. 1H NMR (400 MHz, CDCl3) δ ppm: 2.10-2.21 (4H, m), 2.41 (3H, s), 2.53 (2H, td, J=11.81, 3.41 Hz), 2.99 (2H, d, J=12.38 Hz), 7.32-7.38 (1H, m), 7.39-7.45 (2H, m), 7.49-7.54 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12]
Reactant: OCc1n[nH]c2ccc(Br)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A solution of (5-bromo-1H-indazol-3-yl)-methanol (0.267 g, 1.18 mmol) in ethyl acetate (12 mL) was added with manganese dioxide (1.03 g, 11.8 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and then the filtrate was concentrated to obtain 5-bromo-1H-indazole-3-carbaldehyde (0.179 g, 67%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][CH2:13]Br)=[CH:10][CH:9]=1)([O-:7])=[O:6].C(N(CC)C(C)C)(C)C.ClCCl>CN(C)C=O.O>[CH3:2][N:3]([CH3:4])[CH2:13][CH2:12][C:11]1[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 50.4 %

Procedure:
Dimethylamine hydrochloride (0.390 g, 4.78 mmol) was added to a solution containing 4-nitrophenethyl bromide (1.0 g, 4.35 mmol) and N,N-diisopropylethyamine (1.69 g, 13.05 mmol) in anhydrous dimethylformamide (20 mL). The reaction mixture was heated to 60° C. for 5 hours, then allowed to cool. The solution was diluted with 1:1 water:dichloromethane (200 mL), then added to a separatory funnel. The organics were collected and the product was extracted with 1N aqueous hydrogen chloride. The organics were removed and the aqueous layer was made basic with 1N aqueous sodium hydroxide. The product was extracted with dichloromethane (100 mL) and washed with saturated aqueous sodium chloride (200 mL). The organics were dried over magnesium sulfate and the solvent removed at reduced pressure to afford the title intermediate (0.426 g crude) as a clear oil, which was used without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Product: Fc1c(-c2ccncc2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 7.64-7.70 (2H, m), 7.95-8.01 (2H, m), 8.37 (1H, s), 8.39 (2H, s), 9.05-9.07 (2H, m), 9.40 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.ClC1C=C(Cl)C(Cl)=CC=1[N+]([O-])=O.[Cl:28][C:29]1[C:49]([Cl:50])=[CH:48][C:32]([NH:33][C:34]2[S:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[C:35]=2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:31]([N+:51]([O-])=O)[CH:30]=1.Cl.O.O.[Sn](Cl)Cl>C(O)C.CS(C)=O>[NH2:51][C:31]1[CH:30]=[C:29]([Cl:28])[C:49]([Cl:50])=[CH:48][C:32]=1[NH:33][C:34]1[S:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.0 g), 2,4,5-trichloronitrobenzene (6.8 g) and dimethyl sulfoxide (70 ml), crude crystals (10.3 g) of ethyl 2-(4,5-dichloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (100 ml), 18%hydrochloric acid (100 ml) and tin(II) chloride-dihydrate (22.8 g), ethyl 2-(2-amino-4,5-dichloroanilino)benzo[b]thiophene-3-carboxylate (5.3 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:8]3[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=3)[CH:22]=[CH:21][CH:20]=4)=[O:25])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc12
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc12

Procedure:
This compound is synthesized analogously to example 1 from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 119 (see example 80) and amine 56.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=1)#[N:5]>CCO>[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:2][NH2:3])=[O:11])=[CH:8][CH:7]=1)#[N:5]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
Add hydrazine monohydrate (5.50 mL, 110 mmol) to a solution of methyl 4-cyanobenzoate (3.30 g, 20.5 mmol) in 20 mL of EtOH. Heat the mixture at 80° C. for 1 h resulting in a solution. Cool the mixture to room temperature, causing a solid to precipitate from solution. Collect the precipitate by filtration, wash with cold EtOH followed by diethyl ether to provide 1.90 g, 58% yield of 4-cyano-benzoic acid hydrazide as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:20]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1)(=O)[CH3:21]>ClCCl.CO>[CH3:17][O:16][C:8]1[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:3]([C:4]([N:5]=[C:20]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH2:25][CH2:24]2)[CH3:21])=[CH:6][C:7]=1[O:18][CH3:19])[C:1]#[N:2]
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 10(g) (73%). Rf 0.16 (dichloromethane:methanol 95:5, v/v). MS m/z 514 (MH)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[CH:9]=[N:8]1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[CH:9]=[N:8]1
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (8.7 g, 30.5 mmol) in ethanol (2 mL) was added 3 N NaOH (30.5 mL, 92 mmol). After the reaction was stirred at room temperature for 1 hour, the solvents were evaporated and 3N aq. HCl was added. The resulting solids were collected by filtration to afford 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (5.58 g, 21.7 mmol). The compound had an HPLC retention time=2.0 min. —Column: PHENOMENEX® Luna 5u C18 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(OC)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(OC)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from {2-[3-((S)-2-methoxy-1-methyl-ethoxy)-5-(4-methoxy-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13](CF)[N:14]=1)=[O:7])(C)(C)C.[F:17][C:18](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(O)=O>[F:17][CH2:18][N:14]1[CH:13]=[CH:12][S:11][CH:10]1[CH2:9][NH:8][CH:6]=[O:7]
Reactant: CC(C)(C)OC(=O)NCc1nc(CF)cs1
Reactant: O=C(O)C(F)(F)F
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=CNCC1SC=CN1CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.66 g of the above-obtained 2-(tert-butoxycarbonylamino)methyl-4-fluoromethylthiazole was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate to adjust the pH of the mixture to approximately 8. To this reaction solution was added 20 ml of dichloromethane. To the mixture was added with stirring a solution which had been prepared in advance by reacting 0.33 ml of formic acid with 0.33 ml of acetic anhydride at 50° C. for 10 minutes, and the resulting mixture was stirred at room temperature for an additional one hour. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.27 g of crude 3-fluoromethyl-2-(formylamino)methylthiazole. This compound was dissolved in 6 ml of dichloromethane. 4.2 ml of phosphorus oxychloride was added to the solution at -20° C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue was added 4.2 ml of phosphorus oxychloride, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and then concentrated to dryness under reduced pressure. The residue was dissolved in 10 ml of water, and the solution was washed with 5 ml of dichloromethane. To this was added a saturated aqueous solution of sodium hydrogencarbonate to adjust the pH to approximately 8. The mixture was further extracted with dichloromethane (10ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.241 g (yield 58%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:19]([OH:21])=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:22][C:23]1(C)OC(=O)CC(=O)[O:24]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:12]([CH:11]1[C:19]([OH:21])=[CH:22][C:23](=[O:24])[N:10]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: N#Cc1ccc(N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)phenylalanine (2.0 g), Meldrum's acid (1.05 g) and 4-(N,N-dimethylamino)pyridine (1.22 g) in tetrahydrofuran (30 mL) was added N,N′-carbonyldiimidazole (1.29 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from tetrahydrofuran-hexane to give the title compound as pale-yellow crystals (yield: 1.41 g, 65%).
Reaction SMILES: C(O)(=O)C.[C:5]([NH:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([N+:28]([O-])=O)=[C:13]([CH:27]=1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:7])[CH3:6]>[Fe].O>[C:5]([NH:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([NH2:28])=[C:13]([CH:27]=1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:7])[CH3:6]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Temperature: 80 °C
Yield: 72.8 %

Procedure:
Into a mixture of 40 ml of acetic acid and 40 ml of water was added 2.2 g of an iron powder, and the mixture was heated to 80° C. Into the mixture was added 3.0 g of methyl [2-(5-acetylamino-4-fluoro-2-nitrophenoxy)phenoxy]acetate, and the mixture was heated for 30 minutes under reflux. Thereafter, the mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain 2.01 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
4-Morpholinylcarbonyl chloride (35 μl, 0.3 mmol) was added dropwise to a ice-cooled mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol) and diisopropylethylamine (63 μl, 0.36 mmol) in dichloromethane (5 ml). At the end of the addition, the mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine and dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 1% to 2% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (100 mg, 64%).