Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:19])=[N:17][CH:18]=2)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:22]([C:32]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)[CH2:34][CH2:33]1)[CH:23](N1C(=O)CCC1=O)O>C(O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:22]([C:32]4([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[N:41]=[CH:40][CH:39]=[CH:38]6)[CH2:34][CH2:33]4)=[CH:23][N:19]=3)[CH:18]=2)=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cnc(N)nc2)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Temperature: 105 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of tert-butyl[3-(2-aminopyrimidin-5-yl)-1H-pyrazol-1-yl]acetate (16 mg, 0.058 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (20 mg, 0.058 mmol) in ethanol (0.3 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (10 mg, 37%). LCMS: (M+H)=467.0.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.CN1CCOCC1.[CH2:29]([O:31][C:32]([C@@:34]1([NH2:39])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:33])[CH3:30]>>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:39][C@:34]1([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: -23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF 2.03 mL (20.0 mmol) of NMM was added. A suspension was formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformiate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of NMM was added. To this mixture the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 was added at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. Salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of EtOAc. The extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:18]N(C)CCCN=C=NCC>CO.CCOCC.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (2.2 g, 10 mmol, 1 equiv) in MeOH/Et2O (1:1, 20 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.3 g, 12 mmol, 1.2 equiv), DMAP (112 mg, 1 mmol, 0.1 equiv) and the resulting mixture was stirred at room temperature for 16 h then diluted with AcOEt. The organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 3-amino-5-(2-oxo pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (1.6 g, 68%) as a white solid.
Reaction SMILES: [OH-:1].[K+].F[C:4]1[C:5](=[O:30])[N:6]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20](OCC)=[O:21])[CH:7]=[C:8]([F:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:31]1[CH2:35]CCC1.CO.O>>[F:16][C:8]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([O:31][CH3:35])[C:5](=[O:30])[N:6]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([OH:1])=[O:21])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(-c2ccccc2)c(F)cn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Potassium hydroxide (100 mg, 1.78 mmol) was added to a solution of ethyl (2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (77 mg, 0.19 mmol) in tetrahydrofuran:methanol:water (2:2:1 10 mL). The solution was heated to 50° C. and stirred at this temperature for 4 h. The reaction was concentrated and the residue was dissolved in 1 N aq NaOH (50 mL). The aqueous layer was washed with EtOAc (3×50 mL) and acidified to a pH of 3 using concentrated HCl. The solid was collected via filtration and was washed with water (30 mL) and hexanes (30 mL) to afford the title compound as a white solid (70 mg, 95%). MS (LCMS) m/z 398.0 (M+1). 1H NMR (400 MHz, METHANOL-d4) ppm 1.69-1.79 (m, 3 H) 2.30-2.46 (m, 1 H) 2.55-2.72 (m, 1 H) 3.18 (s, 3 H) 3.66 (s, 3 H) 4.08-4.22 (m, 1 H) 4.23-4.38 (m, 1 H) 7.39-7.51 (m, 5 H) 7.60 (d, 1 H).
Reaction SMILES: C([O:9][CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13])(=O)C1C=CC=CC=1.[OH-].[K+].OC(CCCC)CC#C.C(OCC)(=O)C>CO.O>[OH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(CCCC)OC(=O)c1ccccc1
Agent: C#CCC(O)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#CC[C@@H](O)CCCC
Reaction time: 24 h

Procedure:
A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyl-oxy-1-octyne (Example 141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]D25 = +17+ 1.0° (C=0.77, ethyl acetate). This compound has the (S)-configuration.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 367 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1.C(N(CC)CC)C.O>ClCCl>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:11][CH:12]([NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:24])[CH2:13]2)=[O:35])[CH2:30][CH2:29]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Temperature: 25 °C

Procedure:
At 0° C., 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 1.5 ml of dichloromethane, and 89 mg (0.55 mmol) of 4-methylpiperazine-1-carbonyl chloride and 58 μl (0.412 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 104 mg (77% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([O:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)=[CH:12][CH:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O.[Pd]>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][C:19]([CH3:21])([CH3:22])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]2)=[CH:12][CH:13]=1
Reactant: COc1cc(Cl)ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2cn[nH]c2)ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 160 °C
Yield: 0 %

Procedure:
SiliaCat® DPP-Pd (0.37 g, 0.10 mmol) was added to a microwave vial containing a mixture of 3-(4-chloro-2-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (0.36 g, 0.96 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.4 mmol), and K2CO3 (0.53 g, 3.8 mmol) in ethanol/water (10:1, 6.6 mL). The reaction mixture was sealed, then heated in a microwave reactor at 160° C. for 1 h. After cooling, the reaction was purified by solid phase extraction (5 g SiliaBond Carbonate®, MeOH as eluent). The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel saturated with Et3N, 2 to 25% MeOH in DCM) to give the desired product (0.08 mg, 21%). [M+H]: 408.4; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.33 (bs, 1H), 8.05 (bs, 1H), 7.94 (d, J=9.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.34 (dd, J=8.0, 1.5 Hz, 1H), 7.14 (d, J=9.5 Hz, 1H), 5.57-5.74 (m, 1H), 3.90 (s, 3H), 2.00-2.14 (m, 2H), 1.17-1.31 (m, 8H), 1.11 (s, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:14][CH:15]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]1)=[O:31])([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:29][C:30](=[O:31])[NH:32][CH2:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([C:40](=[O:41])[NH:24][CH:16]([C:13]2[S:14][CH:15]=[C:11]([Br:10])[CH:12]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:38][CH2:39]1)([CH3:25])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: NC(Cc1ccccc1)c1cc(Br)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C. under N2, diisopropylethylamine (1.1 mL, 6.6 mmol) was added dropwise to a mixture of 1A (564 mg, 2.0 mmol), Boc-tranexamic acid (565 mg, 2.2 mmol), HOBt (297 mg, 2.2 mmol), and EDCI (422 mg, 2.2 mmol) in anhydrous DMF (15 mL). After addition, the mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water, 1.0 N HCl, sat. NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel provided 1B as a light yellow solid. LC/MS m/z 521.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 0.8-0-1.0 (m, 2H), 1.45 (s, 9H), 1.25-1.45 (m, 2H), 1.70-1.85 (m, 2H), 1.90-2.05 (2H), 2.95 (2H), 3.05-3.25 (2H), 4.60 (s, broad, 1H), 5.55 (m, 1H), 5.75 (m, 1H), 6.8 (s, 1H), 7.1 (s, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.2-7.35, (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1>ClCCl.C(N(CC)CC)C.S(Cl)(C)(=O)=O>[CH2:1]([O:8][C:9](=[O:21])[CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][S:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)OCc1ccccc1
Reactant: COc1ccc(S)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(SCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butoxycarbonylamino-3-hydroxypropionic acid benzyl ester (29.5 g) in dichloromethane (300 ml), triethylamine (21 ml) and mesyl chloride (8.6 ml) were added and the reaction solution was stirred for 30 minutes at 4° C. The reaction solution was added to 1 N hydrochloric acid cooling with ice. The obtained yellow oil was dissolved into dichloromethane (300 ml), and diisopropylethylamine (17 ml) and 4-methoxybenzenethiol (12 ml) were added thereto at 4° C. and the reaction solution was stirred for 3 hours at room temperature and concentrated. The residue was purified by column chromatography (n-hexane:ethyl acetate=8:1) to give the title compound (24.8 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[Cl-].[NH4+]>CCO.C1COCC1.O.[Fe]>[NH2:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[Cl:1])[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([NH2:22])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cc(CN(Cc2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc2)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CN(Cc2ccc(Cl)c(N)c2)c2ccccc2)ccc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of product from Example 148C (0.304 g, 0.703 mmol) in EtOH (10 mL), THF (10 mL) and H2O (2.5 mL) was added iron powder (0.393 g, 7.03 mmol), followed by addition of ammonium chloride (0.188 g, 3.52 mmol). The resulting mixture was stirred at 90° C. for 2 hrs and then filtered through celite and washed with ethanol. The filtrate was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and H2O, and the organic layer was dried over anhydrous Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient 0-0.1% MeOH in CH2Cl2 to afford the title compound (0.259 gm, 99%).
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.[ClH:13].CCO[C:17]([CH3:19])=O>ClC1C=CC=CC=1>[Cl:13][C:17]1[CH:19]=[CH:8][C:7]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Cl
Reactant: O=C1CCCC(=O)O1
Agent: [Al+3]
Agent: [Br-]
Solvent: Clc1ccccc1
Product: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of aluminium bromide (300 g, 1.12 mol) in dry chlorobenzene (700 ml) at 4° C. was added a solution of glutaric anhydride (60 g, 0.526 mol) in chlorobenzene (300 ml). The resulting orange/yellow suspension was allowed to warm to RT, stirred overnight, then carefully poured into an ice cold stirred solution of 10% HCl (aqueous 1400 ml). The resulting white suspension was poured into EtOAc (900 ml) and the layers separated. The aqueous layer was washed with EtOAc (2×250 ml). The combined organic layer was washed with brine (1×400 ml), dried (MgSO4) and the solvent removed in vacuo to give a yellow/white solid (115.74 g). Recrystallization from toluene/hexane (2:1, 750 ml) gave the title compound (95.14 g) as off white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Mn]([O-])(=O)(=O)=[O:15].[Na+].[OH2:20]>C(O)(C)(C)C>[Cl:1][C:2]1[C:6]([C:7]([OH:15])=[O:20])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: O
Reactant: Cc1cn(-c2cccnc2)nc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C

Procedure:
In another embodiment, 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3) is further oxidized by sodium permanganate in water and tert-butanol and heated at about 80° C. The 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) can be isolated and purified by standard techniques.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[C:27]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]2)=[CH:26][C:24]([NH2:25])=[C:23]([NH:38]C)[CH:22]=1.[CH3:40]C(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[N:25]([CH3:40])[C:24]3[CH:26]=[C:27]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]4)[C:21]([Cl:20])=[CH:22][C:23]=3[N:38]=2)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CNc1cc(Cl)c(N2CCC(C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 80 °C
Reaction time: 5.5 h

Procedure:
N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (120 mg, 0.4 mmol) was added to (4-chloro-2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (110 mg, 0.4 mmol) in DMF (2 mL). After 3 h at rt DIC (74 μL, 0.5 mmol) was added to the reaction mixture and it was stirred at 80° C. for 5.5 h. Additional DIC (40 μL, 0.3 mmol) was added and stirring was continued at 100° C. overnight. The reaction mixture was concentrated and the crude was purified by chromatography to give the title compound.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:10]([S:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:9]=2)[N:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[OH-].[K+]>N1C=CC=CC=1.CO>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[S:19][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:3]([NH:2][S:29]([CH3:28])(=[O:31])=[O:30])[S:4][CH:5]=2)[CH:18]=[CH:17][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1Sc1ccc(F)cc1F
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)c(Sc3ccc(F)cc3F)c2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A mixture of 4'-(2-amino-4-thiazolyl)-2'-(2,4-difluorophenylthio)methanesulfonanilide hydrobromide (1.2 g) and methanesulfonyl chloride (0.556 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, dried and evaporated. The residue obtained was dissolved in methanol and treated with potassium hydroxide (0.4 g). The solution was concentrated and the residue was dissolved in water. The aqueous solution was acidified with dilute hydrochloric acid and extracted with chloroform. The extract was evaporated to dryness. The residue (1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (1:1) followed by recrystallization from ethanol to give crystals of 2'-(2,4-difluorophenylthio)-4'-[2-(methanesulfonamido)-4-thiazolyl]methanesulfonanilide (0.26 g).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[OH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44].OS(C(F)(F)F)(=O)=O.[C:58]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[N:71]=[C:72]([NH:79][CH:80]4[CH2:84][CH2:83][CH2:82][CH:81]4[NH2:85])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:66][CH2:65]2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[OH:45][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:44])=[O:42].[C:58]1([N:64]2[CH2:65][CH2:66][N:67]([C:70]3[N:71]=[C:72]([NH:79][C@H:80]4[CH2:84][CH2:83][CH2:82][C@@H:81]4[NH:85][C:6]([C:5]4[O:1][N:2]=[CH:3][CH:4]=4)=[O:8])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:68][CH2:69]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C(O)c1ccno1
Reactant: NC1CCCC1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2)c1ccno1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
0.004 g (0.03 mmol) of isoxazole-5-carboxylic acid (IX), 0.012 g (0.03 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.017 mL (0.10 mmol) of diisopropylethylamine are placed in 1 mL of dimethylformamide, stirred for 0.1 hours at ambient temperature. Then 0.020 g (0.03 mmol) of N-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamine ditriflate (VIII) (chiral) in 1 mL of dimethylformamide are added. The mixture is shaken for 1 hour at ambient temperature. Then the reaction mixture is purified directly by HPLC through an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroacetic acid (B)).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:11][CH2:12][CH3:13])(C)[NH:5][S:6]([NH2:9])(=[O:8])=[O:7].[CH3:15][O-].[Na+]>CO>[CH2:11]([CH:4]1[N:5]([CH3:15])[S:6](=[O:8])(=[O:7])[NH:9][C:3]1=[O:2])[CH2:12][CH3:13]
Reactant: C[O-]
Reactant: CCCC(C)(NS(N)(=O)=O)C(=O)OC
Agent: [Na+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Reaction time: 15 h
Yield: 125.9 %

Procedure:
A solution of N-(aminosulfonyl)-2-propyl-DL-alanine methyl ester (10.66 g; 47.53 mmol) in methanol (100 ml) was added in one portion to a solution of sodium methoxide (prepared from 2.0 g of Na in 100 ml of dry methanol under nitrogen) and the resulting reaction mixture was stirred for 15 hours. The mixture was neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin with stirring (20 minutes), and filtered. The filtrate was concentrated in vacuo to yield an oil which was dried in vacuo (4 hours) to afford 8.96 g (98%) of 4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =propyl;R2 =CH3 ; R3 =H).