Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1Cl>>[C:1]([O:4][CH2:22][C:21](=[O:23])[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1cccc(Cl)c1
Yield: 46 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis 10 of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product (1.22 g, 46% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.72 (s, 2H) 4.69-4.71 (m, 2H) 7.08-7.11 (m, 1H) 7.21-7.23 (m, 1H) 7.26-7.29 (m, 2H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C(OCC)(=O)C>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC(F)(F)F)C3)nc1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 4-bromo-1,1,1-trifluorobutane (0.248 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 394.2 (M+H)+, HRMS calcd for C20H23N3O2F3 394.1742 (M+H)+, found 394.1733, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TEA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.1 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](N2C=CN=C2)=[O:12])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:22][C:21](=[O:30])[NH:20]1.C1CCN2C(=NCCC2)CC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([N:20]2[C@@H:19]([CH3:18])[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]2=[O:30])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C([C@@H]1C[C@@H]1c1ccc(Br)cc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
A mixture of (cis)-1-{[2-(4-bromophenyl)cyclopropyl]carbonyl}-1H-imidazole (1 eq) from Step 1, (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.2 eq) or (−)-isomer and DBU (added at 0° C., 1.2 eq) in CH3CN (0.2M) was stirred at 0° C. for 4 h. The solvent evaporated and residue purified by flash chromatography (Hexane:EtOAc; 100:0 to 80:20) to afford each diastereoisomer.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C([O-])(=[O:26])C.[K+].[OH-].[Na+]>O>[OH:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A 750 ml flask is charged with 54.4 g (0.2 mol) of 4′-bromomethyl-biphenyl-2-carbonitrile and 250 ml of toluene. To this suspension is added a solution of 30 g (0.3 mol) of potassium acetate in 15 ml of water. The heterogeneous mixture is heated up to an internal temperature of 90° C. to become a clear biphasic solution. After 12 hours at an internal temperature of 90° C. the conversion to the OAc derivative is complete. The biphasic mixture is cooled down to internal temperature of about 50° C. followed by addition of 150 ml NaOH (2N). The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.). After 5 hours at this temperature the PTC saponification is complete (100% conversion, HPLC). Additional 150 ml toluene is added and the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7. The toluene phase is evaporated under reduced pressure and the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC) and a water content of 0.23%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:16][S:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: BrCc1ccccc1
Product: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Yield: 87 %

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was prepared according to the method described by Jiong Jack Chen et al. (Organic Process Research and Development, 2003, 7, 313-317) from 1 g (4.32 mmol) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride and 0.51 mL (4.32 mmol) of bromomethyl-benzene. After filtration and washing with acetone, 1.08 g (87%) of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH:41]1[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]1[C:50]([O:52][CH3:53])=[O:51]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([N:41]4[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]4[C:50]([O:52][CH3:53])=[O:51])=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Reactant: COC(=O)[C@@H]1CN[C@@H](C(=O)OC)C1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](C(=O)OC)N(C(=O)c2ccc(CCC3CNc4nc(N)nc(O)c4C3)s2)C1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a sample of 225 mg (0.70 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.5 mL anhydrous dimethylformamide and 0.08 mL (0.72 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature and 135 mg (0.77 mmol) 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction was stirred for 0.5 hours at room temperature, and 213 mg (1.14 mmol) of trans-dimethyl pyrrolidine-2,4-dicarboxylate were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 185 mg (54%) of trans-dimethyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylcarbonyl}pyrrolidine-2,4-dicarboxylate as a tan solid. Mass Spectrum (FAB+): M+1=490; 1H NMR (300 MHz, DMSO) δ: 1.54-1.64 (m, 3H); 1.76-1.84 (m, 1H); 2.11-2.29 (m, 3H); 2.36-2.43 (m,--1H); 2.72-2.79 (m, 1H); 2.86-2.88 (m, 2H); 3.07-3.23 (m, 2H); 3.61 (s, 6H); 3.95-4.08 (m, 2H); 4.49-4.54 (M, 1H); 5.92 (s, 2H); 6.24 (d, J=1.6 Hz, 1H); 6.91-6.92 (m, 1H); 7.48 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc2c(c1)C(=O)CCC2
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-7-methoxy-1(2H)-naphthalenone starting material was prepared from 7-methoxy-1-tetralone (5.0 g, 28.4 mmol) and N,N-dimethylformamide diethyl acetal (10 ml, 58.3 mmol) ito give the desired product as a yellow solid (1.28 g). m.p. 95.1 °. MS (ES+) 232 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C(OCC)(=O)C(OCC)=O.C(OC(=O)C(=O)CC(=O)COC1C=CC=CC=1)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:64]1[N:65]([CH2:77][CH:78]([NH:80][C:81]([O:83]C(C)(C)C)=O)C)[N:66]=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:64]3[C:81](=[O:83])[NH:80][CH2:78][CH2:77][N:65]3[N:66]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Reactant: CC(=O)COc1ccc(F)cc1
Agent: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Solvent: CCOC(=O)C(=O)OCC
Product: O=C1NCCn2nc(COc3ccc(F)cc3)cc21

Procedure:
The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 3 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 4 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[O:10]([C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]([OH:24])[C:21]([OH:23])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(C)C>[O:10]([C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C@H:20]([OH:24])[C:21]([OH:23])=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(O)c1cccc(Oc2ccccc2)c1
Agent: C[C@H](N)c1ccccc1
Solvent: CC(C)O
Product: O=C(O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Reaction time: 24 h

Procedure:
l-(-)-α-Methylbenzylamine (21.0 g) was added to a solution of racemic 3-phenoxymandelic acid (67.0 g) in isopropyl alcohol (700 ml) and the mixture kept for 24 hours at the ambient temperature. The solid precipitate was collected by filtration, (the filtrate kept -- see below) and recrystallized twice from isopropyl alcohol (200 ml) to yield the l-(-)-α-methylbenzylammonium salt of (S)-3-phenoxymandelic acid, m.p. 153° C. This was then shaken with a mixture of diethyl ether (150 ml) and 5N hydrochloric acid (25 ml), the ether layer separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the ether under reduced pressure to yield a residue of solid (S)-3-phenoxymandelic acid, m.p. 110°-112° C., [α]D25 + 85° (C, 1.5, methanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Reaction time: 8 h
Yield: 152.3 %

Procedure:
NaH (0.082 g, 2.06 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (0.204 g, 1.03 mmol) in dry THF (10 mL). The reaction mixture was stirred at 0° C. for 10 minutes before 2-(trimethylsilyl)ethoxymethyl chloride (0.31 mL, 0.292 mmol) was added dropwise via a syringe. The reaction mixture was left at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and carefully quenched with water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (50:1) to give 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.146 g, 43%) as an oil.
Reaction SMILES: Cl[TeH:2]1[C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14]([C:5]=2[NH:4]O1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[BH4-].[Na+].[C:18](OC(=O)C)(=O)[CH3:19].Cl>O1CCCC1.CO>[CH3:18][C:19]1[Te:2][C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c3ccccc13)NO[TeH]2Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(cc(C)c3ccccc32)[te]1
Temperature: 5 °C
Yield: 32.8 %

Procedure:
3-Chloro-5-methylnaphth[2,1-c][1,2,5]oxatellurazole (Example 4) (16.7 g=0.05 mole) was suspended in a mixture of tetrahydrofuran (THF, 200 ml) and methanol (40 ml) in a 500 ml three necked flask fitted with a nitrogen inlet, a condenser, and a powder addition funnel. Sodium borohydride was added under a nitrogen atmosphere and in small portions until the reaction mixture was a pale orange yellow. This required about 5 to 6 g. The powder addition funnel was then removed and replaced with a stopper. The reaction mixture was then cooled to 5° C. and acetic anhydride (5.1 g=0.05 mole) added slowly through the condenser. The reaction mixture transiently turned a bright orange. Concentrated hydrochloric acid (25 ml) was then added in one portion, the ice bath removed, and the mixture stirred to room temperature. As the reaction mixture warmed up, a crystalline deposit appeared and was collected by filtration. The crystalline deposit was washed with tetrahydrofuran until the filtrate was colorless and clear. The filtrate was then heated to boiling with a mixture of isopropanol (175 ml) and concentrated ammonium hydroxide (25 ml) and filtered hot with Celite®, the cooled filtrate was diluted with water until crystallization started. A first crop of pale yellow needles (5.06 g), m.p. 110°-112° C. was obtained. A further 1.65 g of product were obtained by two further extractions with the same solvent mixture, giving a total yield of 6.71 g=43.3% of theory. For analysis, the material was recrystallized from isopropanol. This did not change the melting point. Elemental analyses were in agreement with that expected for the structural formula.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:37])[CH:12]1[F:38].[C:39](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>N1C=CC=CC=1>[C:39]([NH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH2:16][O:17][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]([O:37][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]1[F:38])(=[O:40])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ncnc2c1ncn2C1OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)C1F
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2C1OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(OC(=O)c2ccccc2)C1F)c1ccccc1
Reaction time: 8 h
Yield: 198.5 %

Procedure:
Compound 55.2 (18.2 mmol) in pyridine (180 mL) was treated with BzCl (6.33 mL, 54.6 mmol) and stirred overnight. The solvent was removed in vacuo and the solid was dissolved in EtOAc (100 mL) and washed with H2O (2×50 mL). The solution was dried over MgSO4, filtered, and subjected to Combiflash purification (SiO2, 330 g, 0-100% EtOAc-hexanes gradient) which afforded 55.3 as a white solid (13.0 g, 96%, two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([NH:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27]1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([NH:32][CH2:31][CH2:30][NH:29][CH:26]1[CH2:28][CH2:27]1)=[O:7]
Reactant: NCCNC1CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCNC1CC1
Yield: 91.7 %

Procedure:
8.06 g (0.04) mole of 2-methoxy-4-amino-5-chlorobenzoic acid and 7.12 g (0.044 mole) of carbonyldiimidazole are suspended in 80 ml of tetrahydrofuran and kept at 30° C. until the end of gas development. The solution of 5 g (0.05 mole) of cyclopropylethylenediamine in 15 ml of tetrahydrofuran is then slowly added, followed by keeping the temperature at 50° C. for 1 hour. After cooling down, the mixture is poured into water, the solid is removed by filtration and crystallized from alcohol, thus obtaining 13 g (91.7%) of 2-methoxy-4-amino-5-chloro-N-(2-(cyclopropylamino)-ethyl)-benzamide, having a melting point of 152°-3° C. Hydrochloride m.p.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:5]=[C:6]([C:12]2([C:35]([F:38])([F:37])[F:36])[CH2:16][C:15]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:22])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)=[N:14][CH2:13]2)[CH:7]=[C:8](Cl)[C:9]=1Cl>O.CCO>[F:32][C:31]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C:12]2([C:35]([F:37])([F:38])[F:36])[CH2:16][C:15]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)=[N:14][CH2:13]2)[CH:7]=[C:8]([C:35]([F:38])([F:37])[F:36])[CH:9]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(C2=NCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (22 mg, 0.50 mmol) was added to Methyl N-{4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzoyl}glycinate (130 mg, 0.22 mmol) in Water (1 ml) and EtOH (5 ml), and stirred at ambient temperature for overnight. 2NHCl was added into the mixture, and extracted with t-BuOMe three times, and dried over MgSO4. After evaporated, the crude product was got (120.0 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:22]([C:5]1[C:4]2[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:23]
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Temperature: 110 °C
Yield: 57.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (310 mg, 0.745 mmol) and CuCN (200 mg, 2.24 mmol) were added to 5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 136 mg of the title compound. MS: (+) m/z 316.29 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Fourteen g of 2-amino-3-(4-chlorobenzoyl)benzene acetic acid, sodium salt.H2O was dissolved in 150 ml of dimethylformamide and then treated with 30 g of ethyl iodide. The resulting solution was stirred at room temperature for 2.5 hours. The solution was then added to water and the mixture was extracted several times with benzene. The benzene layer obtained was washed with dilute base and water, dried over sodium sulfate and stripped to leave an oil which crystallized on trituration with pet. ether. Recrystallization from ethyl alcohol gave 11.6 g of the titled compound as yellow flakes, m.p. 101°-102° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].Cl.[C:19]([NH:23][NH2:24])([CH3:22])([CH3:21])[CH3:20]>C(O)C.C(N(CC)CC)C>[NH2:17][C:16]1[N:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:24]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=12
Reactant: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCn1c(=O)c2c(N)n(C(C)(C)C)nc2c2ccccc21
Yield: 87.3 %

Procedure:
In a mixture of 60 ml of ethanol and 5 ml of triethylamine, 2.00 g (8.1 mmol) of Compound b and 2.00 g (16 mmol) of t-butylhydrazine hydrochloride were refluxed for 4 hours. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, and the residue was passed through a silica gel column and eluted with a 3:1 (by volume) mixed solvent of hexane and ethyl acetate. The main fraction collected was dried under reduced pressure to obtain 2.11 g (87%) of Compound 7 as a colorless crystal. The product was treated with ethyl acetate saturated with hydrogen chloride to obtain a hydrochloride of Compound 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:45])[NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1>CN(C)C=O>[CH2:38]([O:37][C:35]([NH:34][C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:7](=[O:13])[C:8]2=[O:12])=[CH:32][CH:31]=1)=[NH:45])=[O:36])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.00 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 0.17 g of sodium hydride (60%, oil) was added to the solution, followed by stirring at 50° C. for 30 minutes. Then, the reaction mixture was cooled to room temperature, after which 1.48 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane was added thereto and the resulting mixture was stirred overnight at the same temperature. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain 1.76 g of 4-[3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.