Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH2:33]1>CN(C)C=O.C(#N)C>[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:39]=2[CH2:40][CH2:41][C@@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33]3)[CH2:47][CH2:46]1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at 70° C. for 18 h and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave after crystallization from acetonitrile, 65 mg (30% yield) of the title compound as white crystals: mp 127-128° C.; [α]21D +51° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (14, M+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]>ClCCl.C(OCC)(=O)C>[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(c1sc2cc(O)c(O)cc2c1CBr)N1CCOCC1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1CBr)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (1.02 ml) was added to a solution of (3-bromomethyl-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.35 g) in ethyl acetate (50 ml) and stirring continued at 60° C. for 2 hours. The cooled mixture was washed with water, dried and evaporated to dryness. The product was recrystallized from acetone.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1>>[CH3:11][CH2:10][CH2:9][CH2:13][CH:12]=[CH:1][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH3:2]
Reactant: C1=CCCC=CCC1
Reactant: C1=CCC=C1
Product: CC=CCCCCC=CCCCC

Procedure:
TTD is prepared by reacting 1,5-cyclooctadiene with cyclopentadiene according to reaction II as follows: ##STR6##
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:15]([C:13]2[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=2[CH3:18])[C:16]1=[S:17])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(F)cc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(F)ccc2C)C1=S
Yield: 41.3 %

Procedure:
A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH3:34]>>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: N
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(N)=O
Yield: 88 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ammonia to give the title compound as a white solid (170 mg, 88%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.50 (s, 1H), 7.56 (br s, 1H), 7.79-7.72 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 10.80 (br s, 1H); Mass spectrum MH+ 446.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.21 g, 30 mmol) in acetone (60 ml) were added ethyl iodide (5.94 g, 38 mmol) and potassium carbonate (4.53 g, 33 mmol), followed by stirring at 50° C. for 5 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate-hexane (1:4)] to give the title compound (5.72 g).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].I>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a mixture of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 65° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was diluted with chloroform, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure and the residue was recrystallized from ligroin to give 11.2 g (77.8%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose, melting at 133°-136° C.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[ClH:15]>O1CCOCC1.O>[OH:1][CH:2]1[CH:6]([Cl:15])[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:3]1
Reactant: Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC(O)C(Cl)C1
Reaction time: 15 h

Procedure:
4.0 g of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine are dissolved in 15 ml of dioxane, and the solution is treated with 50 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted 3 times with 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with aqueous sodium chloride solution, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, 3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine being obtained as a slightly yellow oil.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13](OCCCC)=[O:14]>COCCOC>[N:13]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:14]
Reactant: CCCCON=O
Reactant: C[C@H](Nc1ccccc1)C(=O)O
Solvent: COCCOC
Product: C[C@@H](C(=O)O)N(N=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
N-Phenylalanine (825 mg) in 1,2-dimethoxyethane (20 ml) was treated with n-butyl nitrite (0.64 ml) and the mixture was stirred for 2.5 h and then the solvent was removed to leave crude N-nitroso-N-phenylalanine. This was dissolved in dichloromethane (10 ml), cooled in an ice-bath and treated with trifluoroacetic anhydride (1.06 ml). The mixture was stirred for 1 h and then the solvents were removed, toluene was added and removed using a rotary evaporator. The residue was chromatographed on silica gel eluting with ethanol/chloroform mixtures to give the sydnone (1 g), νmax (CH2Cl2) 1803(sh), 1763(sh), 1734, 1485, 1243, and 1065 cm-1 ; δ(CDCl3) 2.16 (3H,s), 7.51-7.73 (5H, m); Found m/z 176.0590; C9H8N2O2 requires 176.0586. The sydnone in xylene (8 ml) was treated with ethynyltributylstannane and the mixture was heated under reflux for 8 h. After standing for 16 h at room temperature the mixture was diluted with hexane(15 ml) and loaded onto silica gel and eluted with hexane (100 ml) followed by hexane/ethyl acetate mixtures to give 5-methyl-2-phenyl-3-(tri-n-butylstannyl)pyrazole (602 mg), δ(CDCl3) 0.87-1.76 (27H, m), 2.35 (3H, s), 6.25 (1H, s), 7.26-7.47 Found m/z 448. 1900. C22H36N2Sn requires 448. 1900.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:25]([C:24]1[C:23]([CH3:27])=[C:22]2[C:18]([C:19](=[O:28])[O:20][CH2:21]2)=[C:17]([OH:29])[C:16]=1[CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:26]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was added and the reaction was stirred at room temperature. After 20 hours, the reaction was quenched with MeOH (0.3 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484 M++1].
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH:9]1([C:12](=[O:25])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([S:23][CH3:24])[CH:17]=2)=[O:15])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH:9]1([C:12](=[O:25])[C:13](=[CH:3][N:4]([CH3:5])[CH3:6])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([S:23][CH3:24])[CH:17]=2)=[O:15])[CH2:11][CH2:10]1
Reactant: CSc1cc(C(=O)CC(=O)C2CC2)ccc1C
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CSc1cc(C(=O)C(=CN(C)C)C(=O)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl formamide dimethyl acetal (6.0 ml) was added to a solution of 3-cyclopropyl-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (8.71 g) in toluene. The mixture was stirred at room temperature overnight. Further dimethyl formamide dimethyl acetal (2.0 ml) was added and the mixture was stirred and heated at 50° C. for 24 hours. It was cooled and evaporated to dryness to give 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (10.6 g) as a brown oil.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]2=[CH2:18])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.[OH-].[Ca+2].[OH-]>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]32[O:29][CH2:18]3)=[CH:8][CH:7]=1
Reactant: C=C1C(CC)CCC1Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 100 ml of chloroform, 8.0 g of 2-(4-chlorobenzyl)-5-ethyl-1-methylenecyclopentane (the compound No. 129 shown in Table 3) were dissolved, and then 11.6 g of m-chloroperbenzoic acid were added to the thus formed mixture within 5 min, and the whole mixture was stirred for 2 hours at room temperature. In the next place, 11 g of calcium hydroxide were added to the mixture under cooling with iced water, and the whole mixture was stirred for 30 min at room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)=[O:21])[CH2:16][CH2:15]3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.O.[C].[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][CH:28]=4)=[O:21])[CH2:18][CH2:19]3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3cc([N+](=O)[O-])ccc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2c1
Yield: 45 %

Procedure:
To a solution of 455.6 mg (0.97 mmol) of 4-(7-nitro-4-quinazolinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide obtained in Example 322 in 10 ml of ethanol was added a suspension of 100 mg of 10% palladium-carbon in 5 ml of ethanol and 2 ml of water, followed by stirring in a stream of hydrogen at room temperature for 4 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. The residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][CH:16]([OH:17])[CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)CS(=O)(=O)N1CCc2ccc(Cl)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(CC(O)COc1ccccc1)N1CCc2ccc(Cl)cc2C1
Temperature: 25 °C

Procedure:
A suspension of 1-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-3-phenoxyacetone (468 mg, 1.23 mmol) was prepared in MeOH (15 ml), then NaBH4 (77 mg, 1.85 mmol) was added portionwise. The resulting mixture was stirred at RT for 1 h00. The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc (30 ml) and washed with a 1N aqueous solution of HCl (15 ml) and a saturated aqueous solution of NaHCO3 (15 ml). The aqueous layers were extracted with EtOAc (30 ml). The organic layers were combined, dried (MgSO4) and the solvent was removed under reduced pressure. After purification by crystallization in EtOAc/pentane, the title compound was obtained as a white powder (415 mg, 88%). HPLC, Rt: 4.5 min (purity: 99.2%). LC/MS, M+(ESI): 382.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:28][C:29]([O:31]CC)=[O:30])[N:9]=2)[CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:43])[F:44])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:28][C:29]([OH:31])=[O:30])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A mixture of ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate (180 mg, 0.29 mmol), ethanol (10 mL) and 1 N sodium hydroxide (2 mL) was stirred at room temperature for 30 min. The mixture was acidified with 1 HCl to pH 5. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 12 min; Detector, UV 254 nm. 8.6 mg product was obtained. This resulted in 8.6 mg (5%) of 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetic acid formate as a white solid. LCMS (Method 20) [M+H]+=597.2, RT=2.72 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.72 (s, 1H), 9.34 (d, 1H, J=7.2 Hz), 8.69-8.68 (m, 2H), 8.39-8.37 (m, 3H), 7.63-7.60 (m, 2H), 7.51 (d, 1H, J=2.1 Hz), 7.43 (d, 1H, J=9.0 Hz), 7.32-7.22 (m, 2H), 6.99 (t, 1H, J=73.2 Hz), 4.33-4.22 (m, 2H), 3.83 (s, 2H), 3.334 (s, 2H), 3.15-3.07 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:17][NH:18][C:14]([C:10]1[N:11]=[N:12][S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1snnc1C(=O)O
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1nnsc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid (0.66 g, 2.7 mmol) in DMF (10 ml) was treated with TBTU (1.16 g, 3.5 mmol), N,N-diisopropyl ethyl amine (2.29 ml, 13.5 mmol) and methylamine (1.75 ml, 2M THF solution) and stirred at ambient temperature for 5 h. The reaction mixture was partitioned between potassium hydrogen sulfate (30 ml, 10% aqueous solution) and ethyl acetate (60 ml) and extracted. The organic layer was washed with water and brine, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The residue was suspended in dichloromethane, sucked off, and the filtrate was evaporated. The product was obtained after purification of the crude material by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (0.23 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2>O1CCOCC1.CCOC(C)=O>[CH:41]1[C:40]2[CH:4]([CH2:1][O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[C:10]([OH:12])=[O:11])=[O:7])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid (183.0 mg, 0.576 mmol) was suspended in a 4M hydrochloric acid (1440 μl, 5.76 mmol) solution in dioxane at room temperature for 2 h. After solvent evaporation, the crude product was cooled to 0° C. using an ice bath before being dissolved in MeCN (288 μl) and a 2.0M aqueous solution of Na2CO3 (288 μl, 0.576 mmol). (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (194 mg, 0.576 mmol) was added to the solution and the reaction mixture was allowed to stir for 30 min. The mixture was diluted in 5.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of an aqueous 1N HCl solution. The organic solvents were evaporated and the crude product was then partitioned between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, a yellow crystalline solid was obtained. Purification by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes yielded the desired product as a white crystalline solid. A second purification on silica gel was performed using 100% DCM to 20% MeOH/DCM as eluant. The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a white solid (0.111 g, 44%). 1H NMR (400 MHz, methanol-d4) δ 7.79 (d, J=7.5 Hz, 2H), 7.60 (t, J=6.8 Hz, 2H), 7.47-7.23 (m, 5H), 7.25-7.14 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.52-4.11 (m, 4H), 3.19 (dd, J=14.3, 4.6 Hz, 1H), 2.92 (dd, J=13.9, 9.7 Hz, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:17]=[C:15]1[NH:14][C:13]2[CH:18]=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:11][C:12]=2[O:16]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c2cc(CCO)ccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2oc(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Methanesulfonyl chloride (0.23 ml, 2.93 mmol) was added dropwise, at room temperature, to a solution of alcohol (b) (0.5 g, 2.79 mmol) and triethylamine (0.41 ml, 3 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours. More methane sulfonyl chloride (0.1 ml) and triethylamine (0.1 ml) were added and stirring was continued over night. The same amount of reagent was added yet again and stirring continued for 2 hours. The solvent was then concentrated, the residue was suspended in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. The solid residue was chromatographed on silica gel eluting with heptane-ethyl acetate (1-1) to give the product (0.2 g, 28%).