Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O)(C)C.C(OC(C)C)(C)C>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: Cc1c(SCCCC2NCCc3ccccc32)ccnc1CSc1ccncc1
Yield: 36 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1,2,3,4-tetrahydroisoquinoline, chromatography on silica gel and subsequent crystallization from isopropanol/diisopropyl ether gives the title compound; m.p. 190-192° C.; yield 36% of theory.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH3:13])[N:9]=[C:8]([C:14]([NH2:16])=O)[CH:7]=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH3:13])[N:9]=[C:8]([C:14]#[N:16])[CH:7]=1
Reactant: CCCn1nc(C(N)=O)cc1CCCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCn1nc(C#N)cc1CCCCCl
Yield: 18139.9 %

Procedure:
5-(4-Chlorobutyl)-1-propyl-1H-pyrazole-3-carboxamide (30.95 g, 0.127 mmol) in toluene (250 mL) was treated with phosphorous oxychloride (24.86 mL, 0.267 mol). The solution was heated at reflux for 40 minutes. The reaction was worked-up as described in Part D of Examples 37-39, with the exception that chloroform was used in place of methyl tert-butyl ether, to yield 5.20 g of 5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile as an oil. 1H-NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 4.04 (t, J=7.3 Hz, 2H), 3.62-3.53 (m, 2H), 2.70-2.58 (m, 2H), 1.94-1.76 (m, 6H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[O:17]=[C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([F:6])([F:21])[F:22])=[CH:9][CH:10]=1)[CH2:4][C:3]#[N:5]
Reactant: CCOC(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)CCc1ccc(C(F)(F)F)cc1
Yield: 52.5 %

Procedure:
To a suspension of sodium hydride (40 mmol) in THF (50 ml) was added acetonitrile (5.2 ml, 100 mmol) dropwise. The the resulting anion was added a solution of ethyl 3-[4-(trifluoromethyl)phenyl]propanoate (34.4 mmol) in THF (10 ml). The reaction mixture was refluxed for 3 h and then allowed to cool. To the resulting slurry was added water (50 ml) and the solution was acidified to pH 2 with 6 N HCl. The aqueous solution was extracted three times with diethyl ether. The organic layer was dried (Na2SO4) and concentrated. The product was purified by silica gel column chromatography (silica gel/25% ethyl acetate in petroleum ether) giving A as an oil (4.36 g, 53% yield). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H), 7.31 (m, 2H), 3.44 (s, 2H), 2.99 (s, 4H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].C([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=O)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][OH:21])[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Reactant: CC(=O)OCCCCCBr
Product: O=C(Nc1nccs1)c1cn(CCCCCO)c2ccccc12

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 5-bromopentyl acetate as R5X.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To (S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid (721 mg, 1.69 mmol), tert-butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylcarbamate (595 mg, 2.04 mmol), and N,N-diisopropylethylamine (0.9 mL, 5.2 mmol) in THF (20 mL), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (1.29 g, 3.40 mmol) was added in one portion. The reaction was stirred at ambient temperature for 16 hours. After this time, the reaction was dry loaded onto silica and purified by silica gel column chromatography eluting with hexanes to ethyl acetate to afford (S)-tert-butyl 1-(9H-fluoren-9-yl)-24,24-dimethyl-3,8,22-trioxo-2,12,15,18,23-pentaoxa-4,9,21-triazapentacosane-5-carboxylate (1.17 g, 99%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.62-7.59 (m, 2H), 7.44-7.38 (m, 2H), 7.36-7.26 (m, 2H), 6.78 (bs, 1H), 6.07 (bs, 2H), 5.77 (bs, 1H), 4.42-4.38 (m, 2H), 4.27-4.17 (m, 2H), 3.80-3.70 (m, 2H), 3.68-3.46 (m, 9H), 3.31-3.12 (m, 4H), 2.37-2.13 (m, 3H), 2.00-1.87 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H); ESI MS m/z=700 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13](OCC)=[O:14].CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][OH:14]
Reactant: CCOC(=O)/C=C/c1ccc2ccccc2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OC/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of (E)-ethyl 3-(2-quinolinyl)-propenoate from Step 1 (2.13 g, 9.40 mmol) in THF (20 ml) at -78° C. was added dropwise a solution of DIBAL (1M in hexane) (3.5 eq). After 10 mins at -78° C., the reaction was quenched with 10 ml of 1M solution of Na+ /K+ tartrate and the mixture was allowed to warm to r.t. It was then processed in the usual manner with EtOAc and H2O. The residue was swished with EtOAc/hexane (1:2) to afford 1.36 g of the title alcohol.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][N:8]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=[O:26]>C1COCC1>[C:18]([O:17][C:15]([NH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])=[N:8][CH:9]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Reaction time: 0.58 h
Yield: 55 %

Procedure:
Add slowly butyllithium (1.088 mL, 1.741 mmol, 1.6M solution in hexane) to a solution of 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (200 mg, 0.696 mmol) in anhydrous THF (10 mL) at −78° C. Stir the mixture at this temperature for 35 min. Add 3,3-dimethylbutyraldehyde (0.219 mL, 1.741 mmol) and stir the mixture at −78° C. for 3 h. Quench the reaction mixture at −78° C. with brine. Extract the aqueous phase with EtOAc (3×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify The crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (3:2) to afford the desired intermediate as a colorless oil (118 mg, 55%). MS (ES+) m/z: 309 (M+H)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42]>CC#N.CN(C1C=CN=CC=1)C.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])[CH2:18][CH2:17]1)#[N:24]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (30 mg, 0.068 mmol) in MeCN (0.50 mL) was added DIPEA (0.030 mL, 0.17 mmol) and DMAP (12 mg, 0.10 mmol). To this mixture was added isopropylsulfonyl chloride (0.008 mL, 0.1 mmol). The resulting mixture was allowed to stir at ambient temperature for 1 hour before it was diluted with DMSO (1.0 mL) and purified directly by reverse-phase preparative HPLC (using a gradient elution of 0-100% MeCN/water, with 0.1% v/v HCOOH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #37-1. 1H NMR (600 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.47 (s, 1H), 7.54 (br s, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.15 (br s, 1H), 6.80 (t, J=7.8 Hz, 1H), 3.50-3.56 (m, 2H), 3.19 (s, 2H), 2.98-3.10 (m, 2H), 2.38-2.49 (m, 3H), 2.02-2.08 (m, 2H), 1.15 (d, J=6.6 Hz, 6H). LRMS (ESI) calc'd for C20H26N6O3S [M+H]+: 431. Found: 431.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: O=C1N=C(NC(=O)c2ccccc2)N=C2N=CC=C12

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and benzoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH:28]=2)O)=[C:21]([F:47])[N:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]1([S:38]([N:29]2[C:30]3=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[C:35]3[C:27]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=4)=[N:20][C:21]=3[F:47])=[CH:28]2)(=[O:39])=[O:40])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccc(C(F)(F)F)nc3)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(c1)c(Cc1ccc(NCc3ccc(C(F)(F)F)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 105 %

Procedure:
To 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (576, 0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 mL, 2.10 mmol) and trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80° C. for 2 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude compound (577, 90 mg, 100%) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>>[CH3:10][O:9][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:11]
Reactant: COc1cccc(OC)c1C
Reactant: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])c(OC)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.62 g (76.45 mmol) of 2,6-dimethoxytoluene were introduced in portions into 40 ml of concentrated nitric acid cooled to 0° C. After stirring at 0° C. for 15 min, the reaction solution was poured onto 250 ml of ice and extracted 3× with EA. The combined EA extracts were dried over Na2SO4, the solvent was removed in vacuo, and the brown oily residue was purified by means of column chromatography on SiO2 (EA/heptane 1:8). 8.59 g of the title compound were isolated in the form of a red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: COc1ncc(F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ncc(F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a round bottom flask, 5-fluoro-2-methoxy-nicotinic acid (150, 250 mg, 1.46 mmol) was combined with thionyl chloride (3.00 mL, 41.1 mmol) and the suspension was stirred at room temperature for 3 hours. The reaction was concentrated to dryness under vacuum to provide the desired compound, used in the next step without further purification.
Reaction SMILES: CO/N=C(/C1OCCON=1)\C1C=CC=CC=1O[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:13]=1[F:26].[Cl:33]C1C(F)=C(Cl)N=CN=1.ClC1C=CC=CC=1O>>[Cl:33][C:12]1[C:13]([F:26])=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[N:15]=[CH:16][N:17]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Agent: Oc1ccccc1Cl
Product: Fc1c(Cl)ncnc1Oc1ccccc1Cl

Procedure:
Fluoxastrobin may further be prepared as described in Scheme 3. Particularly, 4,6-dichloro-5-fluoropyrimidine (5) is reacted with 2-chlorophenol in an appropriate solvent and in the presence of a suitable base to give intermediate 4-chloro-6-(2-chlorophenoxy)-5-fluoropyrimidine (17) which is further reacted with (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) to give fluoxastrobin.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:32]1[N:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[N:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CC(=O)Nc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)nn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (41.5 mg) and N-(6-chloro-pyridazin-3-yl)-acetamide (25.7 mg) in dioxane (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon for 10 min and (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(11) chloride*methyl-t-butylether complex (CAS-number.: 1028206-58-7; 8 mg) is added. The resulting mixture is stirred for 1 h at 150° C. After cooling to room temperature, the mixture is filtered over basic alumina and eluted with N,N-dimethylformamide/MeOH (9:1; 2 mL). The solvent is evaporated and the residue is purified by preparative HPLC (eluent water (+0.1% NH3)/MeOH) to yield the desired product. HPLC (method 13): tR=0.26 min; Mass spectrum (ESI+): m/z=425 [M+H]+.
Reaction SMILES: [C:1](=[O:20])([O:5][CH2:6][O:7][C:8](=[O:19])[CH2:9][CH2:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])SCC.S(Cl)([Cl:24])(=O)=O>>[CH2:14]([O:13][P:11]([CH2:10][CH2:9][C:8]([O:7][CH2:6][O:5][C:1]([Cl:24])=[O:20])=[O:19])([O:16][CH2:17][CH3:18])=[O:12])[CH3:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(CCC(=O)OCOC(=O)SCC)OCC
Product: CCOP(=O)(CCC(=O)OCOC(=O)Cl)OCC
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of carbonothioate 80 (1.29 g, 3.93 mmol) in ice-cold CH2Cl2 (20 mL) was added sulfuryl chloride (478 μL, 5.89 mmol) and the mixture was stirred at 0° C. for 2 h 35 min, after which the mixture was concentrated to dryness, providing chloroformate 81 as a colorless gum (1.44 g, >quant.) which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.1 Hz, 6H), 2.05-2.14 (m, 2H), 2.68-2.75 (m, 2H), 4.07-4.15 (m, 4H), 5.84 (s, 2H): 31P NMR (162 MHz, CDCl3) δ 30.08 (s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([OH:27])[CH:21]=1)[CH3:17]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([O:27][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:21]=1)[CH3:17]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Temperature: 45 °C
Yield: 14.9 %

Procedure:
Potassium carbonate 6.7 g (48.5 mmol) followed by 4-fluoro benzonitrile 3.3 g (27.2 mmol) in 10 ml of DMF was added to a solution of 3,5-dihydroxy benzoic acid ethyl ester 5 g (27.4 mmol) in 20 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and was then heated to 45° C. for 10 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 6.76 (1H, s), 7.02 (1H, s), 7.36 (2H, d), 7.24 (1H, s), 7.88 (2H, d), 10.3 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
4-Methylbenzaldehyde (1aa, 1.50 ml, 12.7 mmol) and acetone (19, 0.47 ml, 6.4 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.52 g, 13.0 mmol) and water (10 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 1.30 g (78%) of a yellow solid: mp 174-176° C. [expected mp 171-172° C.]; 1H NMR: δ 2.37 (s, 6H), 7.02 (d, 2H, J=15.9 Hz), 7.20 (d, 4H, J=8.0 Hz), 7.50 (d, 4H, J=7.9 Hz), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.6, 124.6, 128.3, 129.6, 132.1, 140.8, 143.0, 188.9.
Reaction SMILES: C[Al](C)C.Cl.[C:6]([O:10][C:11](=[O:15])[CH2:12][NH:13][CH3:14])([CH3:9])([CH3:8])[CH3:7].[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27](OCC)=[O:28])[O:26][C:22]=2[C:21]([F:32])=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[CH3:39])#[N:17].Cl>ClCCl>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]([CH2:14][NH:13][CH2:12][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:15])=[O:28])[O:26][C:22]=2[C:21]([F:32])=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[CH3:39])#[N:17]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CNCC(=O)OC(C)(C)C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)CNCC(=O)OC(C)(C)C)nc2c1C#N
Reaction time: 25 h
Yield: 87.3 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 4.50 ml, 4.63 mmol) was dropwise added at room temperature to a dichloromethane (6 ml) solution of N-methylglycine tert-butyl ester hydrochloride (840 mg, 4.63 mmol), followed by stirring for 25 hours. Subsequently, a dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) was dropwise added, followed by stirring for 23 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain the entitled compound (569 mg, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.C(OC([N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1)=O)(C)(C)C.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:42]4[CH:43]=[N:39][NH:40][CH:41]=4)[N:22]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:5]3=[N:6][CH:7]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (180 mg, 0.358 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (106 mg, 0.360 mmol), [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (29.2 mg, 0.0358 mmol), and potassium phosphate (153 mg, 0.719 mmol) in water (2 mL)/1,4-dioxane (5 mL) was heated at 88° C. After 1 hour, the reaction mixture was cooled to ambient temperature, quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (132 mg, 75%). LCMS calculated for C25H24N5O4S (M+H)+: m/z=490.2. Found: 490.2.