Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:35][C:36]1[CH:45]=[CH:44][C:39]2[O:40][CH2:41][CH2:42][O:43][C:38]=2[CH:37]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:34])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:40]1[C:39]2[CH:44]=[CH:45][C:36]([CH2:35][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[C:22]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][C:18]4=[O:34])[CH2:13][CH2:14]3)=[CH:37][C:38]=2[O:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.9 %

Procedure:
To 2 mL of a chloroform solution containing 83 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 6 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 48 mg of ethyl (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[F:10].[C-:11]#[N:12].[K+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (1 g, 3.73 mmol) in EtOH (30 mL) was added KCN (0.243 g, 3.73 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in EA (80 mL) was washed with H2O (30 mL) and brine (30 mL). The organic layer was dried and concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=10/1) to yield a white solid of 2-(4-bromo-3-fluorophenyl)acetonitrile (0.78 g, 2.96 mmol, 79.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.63 (t, J=7.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 3.92 (s, 2H); ES-LCMS m/z 214.0 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8].[CH3:19][NH:20][CH3:21].[OH-].[K+]>C(O)CO>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CNC
Reactant: O=C(CCCCCBr)N1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CN(C)CCCCCC(=O)N1CCCc2ccccc21

Procedure:
1-(6-bromohexanoyl)-1,2,3,4-tetrahydroquinoline, (4.9 g), prepared in a manner similar to that set forth in Preparation 1, was refluxed, using a dry ice condenser, in a saturated solution of dimethylamine in ethylene glycol (46 ml). After 45 minutes the solution was cooled and added to dilute aqueous potassium hydroxide. The resultant solution was extracted with ether, and the extract was washed, dried and evaporated to yield as an oil 1-(6-dimethylaminohexanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([CH3:6])[NH2:5].[Li+].CC([N-]C(C)C)C.CS(C[C:21]1[N:22]=[CH:23][C:24]2[N:25]([S:34]([CH3:37])(=[O:36])=[O:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)(=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C@:4]([C:21]1[N:22]=[CH:23][C:24]2[N:25]([S:34]([CH3:37])(=[O:35])=[O:36])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)([CH3:6])[NH2:5]
Reactant: COC(=O)[C@H](C)N
Reactant: CS(=O)(=O)Cc1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@](C)(N)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
The Schiffs' base (1.34 g, 7.0 mmol), derived from alanine methyl ester andbenzaldehyde was dissolved in THF (25 mL), and cooled to -76° C. To this was added a solution of LDA (11.6 mL of 10% in n-hexane) in THF (15 mL). After stirring for 30 minutes this solution was treated with 3-(methylsulfonylmethyl)-9-methylsulfonyl-β-carboline (25 Ml in THF) from Step 2, warmed to room temperature and stirred over night. The brown suspension was evaporated in vacuum, the residue dissolved in ethyl acetate and the solution was washed with water, combined with 100 mL 1N HCl and was stirred for 1 hour at room temperature. The organic layer was separated and the aqueous solution was treated with Na2CO3 to pH 8-9. This was extracted with ethyl acetate (2×100 mL), dried overNa2SO4 and the organic solvent was evaporated in vacuum. The residue was flash chromatographed on silica gel using 5% methanol/methylene chloride to yield 2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methyl ester (0.53 g, 21.2%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(I)c1CBr
Temperature: 70 °C
Yield: 96 %

Procedure:
A mixture of 1-chloro-3-iodo-2-methylbenzene (11 g, 44 mmol) in 60 mL CCl4 was stirred at 70° C. and treated with 1-bromopyrrolidine-2,5-dione (12 g, 65 mmol) and dibenzoyl peroxide (1.1 g, 4.4 mmol) slowly. The resulting mixture was refluxed for 15 hours. The mixture was cooled to room temperature, filtered through a plug of Celite, and washed with 10% EtOAc/hexane. The organic was concentrated and purified by column chromatography (0-10% EtOAc/hexane) to give 14 g pink solid.
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].[CH3:14][NH:15][NH2:16]>C(O)C>[NH2:6][C:5]1[N:15]([CH3:14])[N:16]=[C:1]([CH3:2])[C:4]=1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CNN
Reactant: CC(=O)C(C#N)c1ccc(F)cc1
Solvent: CCO
Product: Cc1nn(C)c(N)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
α-Acetyl-4-fluorophenylacetonitrile (65.1 g) and methylhydrazine (30.9 mL) were dissolved in ethanol (320 mL), and the mixture was heated under reflux for 3 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated. The obtained solid was collected by filtration and washed with hexane to give 5-amino-4-(4-fluorophenyl)-1,3-dimethylpyrazole (69.5 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][CH3:20])=[CH:17][CH:18]=2)[CH:3]=1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:17]1[CH:18]=[C:13]([O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:14]=[N:15][C:16]=1[NH:19][CH3:20]
Reactant: CNc1ccc(Oc2cc(F)ccc2C(=O)OC)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1ncc(Oc2cc(F)ccc2C(=O)OC)cc1Cl
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 377D (0.450 g) and N-chlorosuccinimide (0.239 g) was stirred together in N,N-dimethylformamide (10 mL) at room temperature. The reaction was stirred for 48 hours, diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 5-30% ethyl acetate/hexanes over 30 minutes (flow=40 ml/min) provided the title compound.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:27])[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[O:28]1CCCC1.O.[OH-].[Li+].OO>O>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:27])=[O:28])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Combine (S)-4-benzyl-3-(2-(3,4-dichlorophenyl)pent-4-enoyl)-2-oxazolidinone (13.7 g, 34.0 mol), tetrahydrofuran (300 mL), and water (60 mL). Cool in an ice bath. Add lithium hydroxide hydrate (1.7 g, 71.0 mmol) and an aqueous solution of hydrogen peroxide (12 mL, 30% 140 mmol). After 2 hours, quench by the addition of an aqueous 10% sodium thiosulfate solution (100 mL). Add an aqueous 1 M sodium hydroxide solution and extract twice with diethyl ether. Cool the aqueous layer in an ice bath, acidify with an aqueous concentrated hydrochloric acid solution (about 20 mL), and extract twice with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([CH:27]=[O:28])=[N:10]1.CC(C)=[O:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:27]([OH:31])=[O:28])=[N:10]1
Reactant: O=Cc1nn(-c2ccc(F)cc2F)c2c1CCCCC2Cc1cccc(F)c1
Reactant: CC(C)=O
Product: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1CCCCC2Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Jone's Reagent (5.75 mL, 8.6 mmol) was added to a solution of 1-(2,4-difluoro-phenyl)-8-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole-3-carbaldehyde Compound 1h (1.65 g, 4.31 mmol) in acetone (20 mL) at 0° C. under a N2 atmosphere. The resulting suspension was stirred overnight, while warming to r.t., then filtered through a pad of celite to afford 1-(2,4-difluoro-phenyl)-8-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole-3-carboxylic acid Compound 2a as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][Si:26]([C:29]#[C:30][C:31]1[NH:35][C:34]([C@@H:36]2[CH2:41][C@@H:40]3[C@@H:38]([CH2:39]3)[NH:37]2)=[N:33][CH:32]=1)([CH3:28])[CH3:27].[CH3:42][O:43][C:44]([NH:46][C@@H:47]([CH:51]([CH3:53])[CH3:52])[C:48](O)=[O:49])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:52][CH:51]([CH3:53])[C@H:47]([NH:46][C:44](=[O:45])[O:43][CH3:42])[C:48](=[O:49])[N:37]1[C@H:36]([C:34]2[NH:35][C:31]([C:30]#[C:29][Si:26]([CH3:27])([CH3:28])[CH3:25])=[CH:32][N:33]=2)[CH2:41][C@@H:40]2[C@H:38]1[CH2:39]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[Si](C)(C)C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (428 mg, 1.125 mmol) was added to a stirred solution of (1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (212 mg, 0.865 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (197 mg, 1.125 mmol) in DMF (3 mL) and DIPEA (1.2 mL, 6.9 mmol) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and then purified with a BIOTAGE® Horizon (25 g SiO2, 40-60% EtOAc/hexanes) to yield methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (203 mg) as a yellow glass. LC-MS retention time 3.095 min; m/z 403.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 7.17 (br. s., 1 H), 5.04-5.11 (m, 1 H), 4.54 (d, J=6.8 Hz, 1 H), 3.65 (s, 3 H), 3.54-3.61 (m, 1 H), 2.82 (s, 1 H), 2.39-2.50 (m, 1 H), 2.27-2.36 (m, 1 H), 2.04-2.15 (m, 1 H), 1.94-2.04 (m, 1 H), 1.11 (dt, J=8.7, 5.6 Hz, 1 H), 0.95 (d, J=6.8 Hz, 3 H), 0.90 (d, J=6.8 Hz, 3 H), 0.73-0.79 (m, 1 H), 0.21 (s, 9 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a solution of 2′-bromoacetophenone (15 g, 74.6 mmol) in 150 ml MeOH under argon at room temperature was added NaBH4 (4.23 g, 0.11 mol). The reaction mixture was stirred at room temperature for 24 h then quenched by addition of water. HCl 5 N was added until pH 6-7. MeOH was evaporated. The residue was dissolved in ether and washed once with water, once with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (eluent: heptane: ethylacetate 1:1) to yield 14.8 g (99%) of (RS)-1-(2-bromo-phenyl)-ethanol as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy benzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg (60%) of the product was isolated as a solid. HR—MS: m/z Calculated for C17H19F3N2O7S2 485.0659; Found 485.0666.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][O:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:32])(=O)=O>C1C=CC=CC=1>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:18]([C:12]1[C:13]([CH3:17])=[N:14][N:15]([CH3:16])[C:11]=1[O:10][CH2:9][CH2:8][N:1]([CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27]
Reactant: COS(=O)(=O)OC
Reactant: Cc1nn(C)c(OCCNc2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: Cc1nn(C)c(OCCN(C)c2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
2.7 g of 5-(2-anilinoethoxy)-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole prepared by the procedure of Example 1 or 3 was dissolved in 25 ml of benzene, then 0.7 ml of dimethyl sulphate was added and the mixture heated under reflux for 3 hours with stirring. After cooling of the mixture and washing with water, the organic layer was dried over anhydrous sodium sulphate and the solvent distilled off to give 2.4 g of the desired product, Compound 2, similar to that of Examples 2 and 3 (yield 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:19]=[C:18]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:12])[CH2:6][CH2:7][O:8]3)=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1CCOc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCOc2cc(-c3cccc(F)c3)ccc21
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-2H-chromen-4-one (1.5 g, 6.6 mmol), 3-fluorophenylboronic acid (1.39 g, 9.9 mmol) and sodium carbonate (2.1 g, 19.8 mmol) in dioxane (20 mL) and water (1 mL) was added Pd(PPh3)4 (382 mg, 0.3 mmol) at rt. The solution was heated at 100° C. overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM=10:1:2) to give 1.4 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 2.86 (2H, t, J=6.6 Hz), 4.60 (2H, t, J=6.6 Hz), 7.11-7.14 (1H, m), 7.18 (1H, d, J=1.5 Hz), 7.23-7.29 (2H, m), 7.32-7.45 (2H, m), 7.98 (1H, d, J=8.1 Hz).
Reaction SMILES: [Br:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH2:4][CH2:5]C(Cl)=O.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH2:4][CH3:5]
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)Br
Solvent: c1ccncc1
Solvent: CC#N
Product: CCC(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In the second step, a solution of 3-oxo-4,10-oxa-tricyclo[5,2,1,02,6]nonan-(8)9-ol (21.3 g, 125.0 mmol) in 200 mL acetonitrile was added to the 5-bromo-4,4,5,5-tetrafluoropentanoyl chloride solution. To the mixture was added 9.93 g (125.5 mmol) pyridine and the reaction was stirred at ambient temperature under nitrogen for 16 h. The solvent was removed under reduced pressure and the resulting oily residue was dissolved in 250 mL dichloromethane. The later solution was washed once with 200 mL 1 N HCl, washed once with 200 mL saturated aqueous NaHCO3, dried over MgSO4 and the solvent removed under reduced pressure to produce 3-oxo-4,10-oxa-tricyclo[5,2,1,02,6]nonan-(8)9-oxycarbonyl]-4-bromo-3,3,4,4-tetrafluorobutane as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 62 %

Procedure:
To a solution of methyl 3-(4-aminophenyl)propanoate (2.69 g, 15.0 mmol) in pyridine (20 mL) was added 2-nitrobenzenesulfonyl chloride (3.99 g, 18.0 mmol) by small portions, and the mixture was stirred at room temperature for 45 hr. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue. The mixture was stirred with heating at 80° C. for 15 min and filtrated through celite. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate/hexane) to give the title compound (3.39 g, yield 62%) as yellow prism crystals.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[O:4]1.[P:10]([S-:20])([O:16][CH2:17][CH2:18][CH3:19])([O:12][CH2:13][CH2:14][CH3:15])=[S:11].[K+]>CC(C)=O>[P:10]([S:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[O:4]1)(=[S:11])([O:16][CH2:17][CH2:18][CH3:19])[O:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCOP(=S)([S-])OCCC
Reactant: Cc1cc(=O)n(CCl)o1
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOP(=S)(OCCC)SCn1oc(C)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1.48 g of the 2-chloromethyl-5-methyl-4-isoxazolin-3-one thus obtained in 30 ml of acetone were added 2.52 g of crystalline potassium O,O-di-n-propyl dithiophosphate, and the resulting mixture was then stirred for 1 hour at ambient temperature. The acetone was then evaporated off and the residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. There were obtained 2.39 g (73.5% of theory) of O,O-di-n-propyl S-(5-methyl-3-oxo-4-isoxazolin-2-ylmethyl) phosphorodithioate, in the form of a pale yellow oil, n20D =1.5314.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[C:16]1([S:22]([N:8]2[C:9]3[C:5](=[C:4]([CH3:13])[CH:3]=[C:2]([Cl:1])[C:10]=3[O:11][CH3:12])[CH:6]=[N:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1c(Cl)cc(C)c2cn[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-7-methoxy-4-methyl-1H-indazole (1.55 g, 9.2 mmol) is dissolved in THF (50 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) is added and the reaction is stirred 10 min. Benzenesulfonyl chloride (1.2 mL, 9.7 mmol) is added and the reaction is stirred 20 min. The reaction is diluted with EtOAc, washed with a solution of NH4Cl, water, brine and dried with MgSO4. The solution is concentrated and triturated with hexane to provide 1-benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole which is used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[C:30]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (418 mg, 1.56 mmol) and benzyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (500 mg, 1.74 mmol) were dissolved in tert-butanol (8 ml) and DIEA (2 ml, 11.45 mmol) was added. After stirring the mixture at 80° C. for 12 h, the solvent was evaporated under reduced pressure and the residue was suspended in water, basified with sodium carbonate and extracted with AcOEt (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 560 mg (66% yield) of the title compound as a white solid. Purity 96%.