Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[N:15]=[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[Cl:25]N1C(=O)CCC1=O>CN(C)C=O>[Cl:25][C:13]1[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 2,6-bis[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 1, Step 1, 186 g, 555 mmol) in anhydrous N,N-dimethylformamide (930 mL) was added a solution of N-chlorosuccinimide (81.5 g, 610 mmol) in anhydrous N,N-dimethylformamide (560 mL) dropwise from a dropping funnel (1 L) during the period of 2.5 h at 70° C. (internal temperature) under nitrogen atmosphere. The resulting pale yellow solution was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction solution was quenched with a solution of 250 g of ammonium chloride and 100 g of sodium hydrogen sulfite in 3 L of water and extracted with a mixture of ethyl acetate and hexane (3 L, 3:1). After the layers were separated, the organic layer was washed with water (2 L), dried over sodium sulfite (300 g) and evaporated. The residual pale yellow solid was added isopropylether (1.4 L) and the resulting mixture was stirred at 60° C. for 2 h. After the mixture was cooled to room temperature, the mixture was filtered through paper filter, and the cake was washed with isopropylether (200 mL), dried under reduced pressure at room temperature to give (153.9 g, 416 mmol) of the title compound as a white solid.
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)CCCCC1.Br[CH2:14][C:15]([NH:17][CH:18]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([NH:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:32]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCNCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.7 %

Procedure:
1-Cyclohexylpiperazine (3.65 g, 22.492 mmoles) was added to a stirring solution of 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (21.369 mmoles) and powdered potassium carbonate (3.56 g, 25.758 mmols) in methylene chloride under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The salts were filtered and the solution concentrated to a brown foam on a rotary evaporator. The desired product was purified on a Prep 500 column using a 10 L gradient starting with 100% methylene chloride and ending with 5% methanol/94.5% methylene chloride/0.5% ammonium hydroxide. Impure fractions were combined and purified further by reverse phase preparative high performance liquid chromatography (methanol/acetonitrile/water/ammonium acetate). After combining the material from both chromatographic purifications the title compound (10.43 g, 18.663 mmoles) was isolated (87% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([C:13]1[O:1][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:12]=1)[CH3:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(NC(=O)C2(C)CCCN2C(=O)OCc2ccccc2)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(C3(C)CCCN3C(=O)OCc3ccccc3)oc12
Temperature: 110 °C
Yield: 31.3 %

Procedure:
A mixture of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (550 mg, 1.33 mmol) in anhydrous toluene (10 mL) was added anhydrous pyridine (0.583 mL, 7.3 mmol), then thionyl chloride (0.39 mL, 7.3 mmol) was added, the mixture was heated to 110° C. for 6 h. The mixture was cooled to room temperature and poured into ice water (100 mL) carefully with vigorous stirring, then extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 8:1) to give methyl 2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxylate (164 mg, yield 32%). 1H-NMR (400 MHz, CDCl3): δ 1.63 (s, 3H) 2.02-2.05 (m, 2H), 2.14-2.16 (m, 1H), 2.40-2.44 (m, 1H), 3.73-3.77 (m, 1H), 3.87-3.90 (m, 1H), 3.94 (s, 3H), 4.71-4.73 (d, J=9.6 Hz, 1H), 5.06-5.09 (m, 2H), 6.79-6.81 (d, J=6 Hz, 1H), 6.89-6.92 (m, 1H), 7.02-7.04 (m, 1H), 7.33-7.37 (m, 3H), 7.80-7.95 (m, 2H); LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]=1[OH:40])(=[O:10])[CH3:9].[CH2:41](N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH2:5][CH3:41])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:34][CH2:35][C:36]([F:37])([F:39])[F:38])[C:12]=1[OH:40])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(COc1ccc(C)c(N)c1)COc1ccc(C(C)=O)c(O)c1CCC(F)(F)F
Reactant: COC(=O)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OCC(COc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)OC(C)=O)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 8.3 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-aniline and 2.9 ml of triethylamine in 70 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 2 hours. The reaction mixture is poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-phenyl}}-oxamate is thus obtained as an oil with an Rf value=0.13 (silica gel; toluene/ethyl acetate=6:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35]O)=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.C1(P([N:59]=[N+:60]=[N-:61])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:59]([CH2:35][C:33]1[S:34][C:30]([C:12]2[C:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)[CH:19]=4)[C:14]=3[N:10]([CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:11]=2)=[CH:31][CH:32]=1)=[N+:60]=[N-:61]
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CO)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN=[N+]=[N-])s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 382 (8.0 g, 13.2 mmol) in tetrahydrofuran (100 mL) was cooled to about 0° C. and diphenylphosphoryl azide (7.1 mL, 33.0 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7ene (4.9 mL, 33.0 mmol) were added slowly in the dark. After the addition was complete, the mixture was stirred for about 2 hours at ambient temperature in the dark. The mixture was basified by addition of potassium carbonate and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrate. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 632 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[CH:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (200 mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (173 mg, 0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) and N,N-dimethylformamide (1 mL) and strirred for 15 min. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mol) dissolved in methylene chloride (5 mL) and diisopropylethylamine (0.14 mL) were added and the mixture was stirred overnight under nitrogen atmosphere. The mixture was diluted with methylene chloride (50 mL), washed with water (50 mL), sodium hydrogen carbonate (30 mL, saturated), and sodium hydrogensulfate (30 mL, 5%). The phases were separated and the organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was chromatographed (silica, 2×40 cm) to afford 450 mg of ((3E)-1,1-dimethyl4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [ClH:1].C(=N)(OCC)C.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1C(=O)N[C:25]([CH3:29])=[N:24]1>C(Cl)Cl.Cl.C(=N)(OCC)C>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:24]=[C:25]([Cl:1])[CH3:29]
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Reactant: Cl
Agent: CCOC(C)=N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A stirred solution of 13.6 grams (0.1100 mole) of ethyl acetimidate hydrochloride and 13.2 grams (0.1300 mole) of triethylamine in 100 grams of methylene chloride was cooled to about 0° C. for five minutes, and 17.7 grams (0.1000 mole) of 2,4-dichlorophenylhydrazine (1) was added. Upon completion of addition the reaction mixture stirred at 0° C. for about one hour, then it was allowed to warm to ambient temperature where it stirred for about two hours. GC analysis of the reaction mixture indicated the presence of a small amount of unreacted (1). An additional 0.6 gram of ethyl acetimidate hydrochloride was added (total 14.2 gram-0.1150 mole), and the reaction mixture was stirred for an additional one hour. After this time the reaction mixture was washed with about 20 mL of water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was triturated with 20 mL of hexane, and the resultant solid was collected by filtration. The solid was washed with 50 mL of hexane and dried, yielding 20.4 grams (93.4% yield) of 2-(2,4-dichlorophenyl)hydrazidethaneimidic acid (A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 93.8 %

Procedure:
Preparation of example 154 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-naphthalen-2-ylpropanoic acid (58 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (69 mg, 0.120 mmol) as a yellow powder in 94% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 92 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-nitro-benzenesulfonamide (2.20 kg, 9.30 mol), benzylamine (1.5 L, 13.9 mol), triethylamine (2.5 L, 18.1 mol), and acetonitrile (22.0 L) were heated at 92° C. for 20 h. The mixture was then cooled to 40° C., and was then partially concentrated in vacuo. The residue was added to 0° C. water (22.0 L) and the resulting suspension was allowed to warm to 23° C. and stirred for 2 h. The suspension was filtered and the solid was then washed with water (5 L). The washed solid was suspended in absolute ethanol (11 L), and was then filtered and washed with absolute ethanol (5 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-benzylamino-5-nitro-benzenesulfonamide (2.40 kg, 7.81 mol, 84%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.64 (2H, d, J=4.6 Hz), 6.81 (1H, d, J=9.4 Hz), 7.23-7.44 (6H, m), 7.77 (2H, bs), 8.11 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 8.49 (1H, d, J=3.1 Hz). LC-MS (ESI) calcd for C13H13N3O4S 307.06. found 308.2 [M+H+](100%), 615.2 [2M+H+] (81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:26][C:15]4([CH2:18][N:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:16]4)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[O:27][CH:28]([C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=1[Cl:38])[CH3:29].C1(C)C=CC=CC=1>C(O)=O>[CH:19]([OH:21])=[O:20].[CH2:16]1[C:15]2([CH2:14][CH:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:4]=[C:3]([O:27][CH:28]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=5[Cl:38])[CH3:29])[C:2]([NH2:1])=[N:7][CH:6]=4)[CH:9]=[N:10]3)[CH2:26]2)[CH2:18][NH:17]1
Reactant: CC(Oc1cc(-c2cnn(C3CC4(C3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CC(Oc1cc(-c2cnn(C3CC4(CNC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (53 mg, 0.094 mmol) was dissolved in formic acid (3 mL). The solution was sonicated at room temperature for 1.0 h and then concentrated by evaporation in vacuo to give the residue. Toluene (2×5 mL) was added and evaporated again. Ether (10 mL) was added and the mixture was stirred at room temperature for 1.0 h. The solid was collected by filtration, washed with ether (10 mL) and then dried under high vacuum to afford (±)-5-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine formate (29 mg, 61%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)(C)(C)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: NC1CC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A solution of 2.7 g (8.0 mmol) of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate, 0.46 g (8.0 mmol) of cyclopropylamine, and 40 ml of dry t-butanol was stirred at 45° C. for 21/2 hours. The mixture was cooled to room temperature and used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:11])=[O:10].[C:12](=O)([O-])[O-:13].[K+].[K+].C[C:19]([CH3:21])=[O:20]>>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:21][C:19]([O:13][CH3:12])=[O:20])=[CH:7][C:2]=1[CH3:1])(=[O:10])[CH3:11]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1ccc(C(C)=O)c(C)c1
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxy-2-methylacetophenone (4.8 g), anhydrous potassium carbonate (5.3 g) and methyl brDmoacetate (3.55 ml) in anhydrous acetone (100 ml) was stirred for 2 days. The mixture, after filtration and evaporation of the solvent, gave methyl 4-acetyl-3-methylphenoxyacetate, 6.6 g, as a crystalline solid: m.p. 49°-50° C.; NMR (d6DMSO) δ 7.84 (1H, d), 6.83 (2H, m), 4.87 (2H, s), 3.71 (3H, s), 2.50 (3H, s), 2.45 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].C(=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26](SCC(O)=O)[CH2:27][OH:28])=[CH:22][CH:21]=1.C1CCCCC1.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][S:5][CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[CH:21][CH:22]=1)[CH2:27][OH:28]
Reactant: O=C(O)CSC(CO)c1ccc(-c2ccccc2F)cc1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)CSC(CO)c1ccc(-c2ccccc2F)cc1

Procedure:
20 gm of the product thus obtained were reacted with 8.75 gm of thioglycolic acid methyl ester and 11.5 gm of potassium carbonate in 70 ml of dimethyl sulfoxide. From the obtained reaction product (oil, Rf -value: 0.4 on carrier 1 with cyclohexane/ethyl acetate = 2:1) [1-(2'-fluoro-4-biphenylyl)-2-hydroxy-ethylthio]acetic acid, m.p. 115°-117° C (from cyclohexane/ethyl acetate = 1:2, was obtained by hydrolysis. Preparation of end products of the formula I:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(COC)=O)[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[CH:19]=1.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][C:20]=1[O:26][C:27]([F:29])([F:28])[F:30])[CH3:2]
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: CCOC(=O)CP(=O)(COC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.5 %

Procedure:
To a solution of (ethoxy-methoxymethyl-phosphinoyl)-acetic acid ethyl ester (3.45 g, 15.4 mmol) in THF (230 mL) was added 60% sodium hydride in oil (370 mg, 15.4 mmol). The mixture was stirred at ambient temperature for 50 min and cooled at 4° C. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (3 g, 11.2 mmol) in THF (100 mL). The mixture was stirred at ambient temperature for 15 hr. The solution was poured into H2O, and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 5% EtOAc in hexane) to give (E)-3-(4-Bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98 g, 79%) as a colorless oil.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:6])[CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](Cl)=[O:26]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25]([N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([CH3:6])[CH3:5])=[O:26]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CNC(C)C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1cc(Cl)cc(Cl)c1)C(C)C
Temperature: 25 °C

Procedure:
A 250 milliliter round-bottom, 3-neck flask was equipped with a condenser, a thermometer, a dropping funnel, and a Teflon® spin-bar magnet for stirring. The outlets were protected from moisture by calcium chloride drying tubes, and the flask was immersed in an ice-water cooling mixture. The flask was charged with an 80 milliliter dichloromethane solution containing 0.015 mole (2.2 grams) of the ethyl N-isopropylaminoacetate (described above) and 0.015 mole (1.5 grams) of triethylamine. The solution was stirred while cooling in an ice-water bath. A 20 milliliter solution of dichloromethane containing 0.015 mole (3.14 grams) of 3,5-dichlorobenzoylchloride was added dropwise over a period of 1.0 hour with stirring and the stirring was continued for several hours followed by allowing the mixture to warm to room temperature. The reaction solution was washed four times with water (25 milliliters) to remove the triethylamine hydrochloride. The washed organic solution was filtered to remove the phase water and concentrated first by rotary evaporation (house vacuum, water bath to 65° C.) to 4.9 grams of a dull yellow syrup (nD20 1.5257) and then, using a vacuum pump (<1 mm, oil bath to 50° to 60° C.) for 1.0 hour, to 4.5 grams (94 percent crude yield) nD20 (1.5280) ethyl N-3,5-dichlorobenzoyl-N-isopropylaminoacetate. It had a mass spectra (m/e) of molecular weight of 317, an infrared spectra (neat) mull technique with ester C=O band at 1745 centimeters-1 and amide (C=O) band at 1635 centimeters-1. It had the following nuclear magnetic resonance values δ (CDCl3) of 1.1 (doublet, 6H, (CH3)2C--), 1.3 (triplet, 3H, CH3--), 3.7-4.5 (4.0 broad singlet, 4.2 quartet, (overlap), 5H, CH2N, CH2, CH (heptet obscured)), and 7.3-7.5 (multiplets, 3H, aromatic).