Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)=O>C1COCC1>[C:18]([NH:17][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of dimethyl methylphosphonate (3.06 mL, 28.27 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.66 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 1 (1.00 g, 3.53 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded dimethyl [(3S)-3-[(N-benzoyl)amino]-2-oxo-4-phenyl-butyl]phosphonate 2 as a pale yellow oil (0.876 g, 66%): Rf 0.34 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 3.10 (2H, m, —CH2Ph), 3.34 (2H, m, —CH2—), 3.69 and 3.73 (6H, 2xs, 2xOMe), 5.10 (1H, m, —CH—) and 7.18-7.82 (10H, m, Ar—H).
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:1]
Reactant: COc1ccc(C)cc1C(=O)c1ccccc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1cc(C)ccc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a suspension of 7.58 g (21.2 mmole) methyltriphenylphosphoniumbromide in 15 ml abs. THF at room temperature within 10 minutes 17.0 ml (21.2) n-butyllithium (1.25M in n-hexane)are added dropwise. The reddish solution obtained is cooled to −78° C. and then within 15 minutes a solution of 3.70 g (16.3 mmole) 2-methoxy-5-methyl-benzophenone in 5 ml abs. THF is added. Agitation is performed initially for 20 minutes at −78° C. and for a further 8 h at room temperature. Then 80 ml water are added to the reaction mixture and extracted twice with 50 ml diethylether in each case. The purified organic phases are then dried through magnesium sulphate and the solvent is removed. Purification of the raw product obtained takes place by column chromatography on silica gel with toluene as the solvent. 3.03 g (13.5 mmole, 83%) 1-methoxy-4-methyl-2-(1-phenyl-vinyl)-benzene are obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:25]=[N+:26]=[N-:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:9]([N:25]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:27]=[N:26]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCOC(=O)C=C
Reactant: CCCCCCCCCCCCCCCCN=[N+]=[N-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Propargyl acrylate (1.10 g, 10 mmoles), hexadecyl azide (2.37 g, 10 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (74 mg, 0.2 mmoles) are dissolved in DMF (20 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (2.95 g; yield 85%; mp 72-73° C.). 1H NMR (CDCl3, δ ppm) 7.61 (s, 1H), 6.44 (d, 1H), 6.14 (dd, 1H), 5.85 (d, 1H), 5.31 (s, 2H), 4.34 (t, 2H), 1.92 (q, 2H), 1.26 (m, 28H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 166.00, 142.73, 131.39, 128.04, 123.64, 57.75, 50.43, 31.89, 30.22, 29.66, 29.65, 29.64, 29.62, 29.61, 29.56, 29.47, 29.33, 29.32, 28.95, 26.46, 22.66, 14.08. MS for C12H39N3O2 calculated 377.58; found 377.20.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1.C([Mg]Cl)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nnc2ccc(Br)cn12
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(C=O)cn12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (0° C.), dark brown solution of 0.48 g of 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine in 5 mL of tetrahydrofuran was added slowly 1.3 mL of 2 M isopropylmagnesium chloride in tetrahydrofuran. After 30 minutes N,N-dimethylformamide was added; the ice bath was removed, and the mixture was heated to 50° C. for 150 minutes. The mixture was cooled to 22° C., diluted with 1 M hydrochloric acid, and stirred for 10 minutes. The mixture was made basic with saturated aqueous sodium carbonate, and extracted with ethyl acetate (3×). The combined extracts were washed with brine (2×), dried (sodium sulfate), filtered, and the filtrate was concentrated to give a light yellow solid which was crystallized (ethyl acetate, hexanes, and methanol) to give 0.19 g of 3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine-6-carbaldehyde as a faint yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.CN([CH:29]=[O:30])C>CCOCC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=2)[CH:29]=[O:30])[CH2:11][CH3:12])=[CH:14][C:15]=1[CH3:20]
Reactant: CCC(Nc1ccc(C)c(Br)c1)c1ccc(Cl)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCC(Nc1ccc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of INT 8 (2.20 g, 14.7 mmol) in Et2O (147 mL) at −78° C. was added tBuLi (1.7 M in pentane, 34.7 mL, 59.0 mmol) dropwise. The mixture was stirred at −78° C. for 40 min, then DMF (2.5 mL) was added. The reaction mixture was stirred at −78° C. for an additional 20 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 9.
Reaction SMILES: [Li][C:2]#[C:3][CH:4]([CH3:6])[CH3:5].[C:7](OCC)(=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1>[CH3:5][CH:4]([CH3:6])[C:3]#[C:2][C:7](=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: [Li]C#CC(C)C
Reactant: CCOC(=O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C#CC(=O)C(=O)OC(C)(C)C

Procedure:
reacting 1-lithio-3-methylbut-1-yne with a 150% to 165% excess of the stoichiometric amount of ethyl t-butyl oxalate in THF containing an amount of a suitable hydrocarbon solvent sufficient to solubilize said 1-lithio-3-methylbut-1-yne, the reaction being carried out under anhydrous conditions in an inert atmosphere at a temperature of from 0° to 10° C. to form t-butyl 5-methyl-2-oxohex-3-ynoate;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[Na].O>C(O)CCC>[NH:1]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH2:2]1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: [Na]
Solvent: O
Solvent: CCCCO
Product: C1=C(CCc2c[nH]c3ccccc23)CCNC1
Yield: 24.8 %

Procedure:
A solution of 10.3 g of 3-[2-(4-pyridyl)-ethyl]-indole (prepared according to U.S. Pat. No. 3,300,506) in 400 ml n-butanol was heated, under nitrogen, at a temperature of approximately 90° C. Thereafter, 8 g of sodium were added portionwise while agitating magnetically and the temperature was raised to and maintained at about 110° C. until the sodium disappeared. Once the ambient temperature had been restored, the solution was poured into 400 ml water, the organic phase washed with water until it became neutral and then was dried over sodium sulfate and evaporated under vacuum. The evaporation residue was mixed with 25 ml absolute ethanol and purified by means of chromatography over silica gel, (eluant: ethanol-diethylamine=40-1). Following two processes of crystallization in methanol, 2.6 g of 3-[2-(1,2,5,6-tetrahydro-4-pyridyl)-ethyl]-indole were obtained, which melted at 155° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCNCCO
Product: OCCN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
From diethanolamine and trityl chloride.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](N)=[N:21][C:20]=2[CH:31]=1.C1(C)C=CC=CC=1>CS(C)=O>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:22]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[NH:25][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:31][C:20]=3[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Clc1ccc2c(c1)N=C(N1CCN[C@@H](Cc3ccccc3)C1)c1ccccc1N2
Yield: 52.3 %

Procedure:
Combine 3-(S)-benzyl-piperazine (800 mg, 4.5 mmol), 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (424 mg, 1.5 mmol), toluene (8 mL), dimethylsulfoxide (2 mL) and reflux for 3 days. Concentrate and pour into water (50 mL), filtrate the resulting solid, redissolve in dichloromethane (200 mL), wash with water and dry over magnesium sulfate. After concentration, purify by flash chromatography (dichloromethane then gradient of methanol 3–10%) to give (316 mg, 53%) of the title compound as a yellow foam: mp 79–92° C.; 1H NMR (CDCl3): δ 2.59 (dd, 1H), 2.90–2.66 (m, 3H), 3.09–2.94 (m, 3H), 3.85 (bm, 1H), 4.03 (bm, 1H), 4.88 (s, 1H), 6.61 (dd, 1H), 6.79–6.84 (m, 2H), 6.97 (t, 1H), 7.06 (t, 1H), 7.35–7.19 (m, 7H); MS (APCI) m/z (rel intensity) 403.4 (100).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][NH2:5].O=C1[NH:12][C:11]2[C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=[CH:16][C:10]=2[C:9](=[O:20])[O:8]1.Cl>O>[NH2:12][C:11]1[C:13]([C:17](=[O:18])[NH:5][CH3:4])=[CH:14][CH:15]=[CH:16][C:10]=1[C:9]([OH:8])=[O:20]
Reactant: O=C(O)c1cccc2c(=O)oc(=O)[nH]c12
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)c1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
Aq NaOH (23.4 mL, 46.8 mmol) was added to a solution of methylamine hydrochloride (3.52 g, 53.7 mmol) in H2O (37 mL). 2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-8-carboxylic acid 29 (3.23 g, 15.6 mmol) was in portions. After addition was complete, the solution was stirred at ambient temperature for 1.5 h. 6M HCl was added until pH=3. The resulting precipitate was collected by filtration, rinsed with H2O and dried to give 31 (2.60 g, 86% yield).
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[CH2:11][CH2:12]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[N:52]([C:54](=[O:57])[NH:55][N:56]=2)[CH:53]=1>C1COCC1>[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[N:52]([C:54](=[O:57])[N:55]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[N:56]=2)[CH:53]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]nc2ccc(Br)cn12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
In a 1-dram vial were placed 2-(quinolin-2-yl)ethanol (405 mg, 2.80 mmol), DIAD (472 mg, 2.34 mmol) and triphenylphosphine (613 mg, 2.34 mmol) in THF (11.7 mL). The mixture was stirred at room temperature for 10 min, and 3-3 (600 mg, 2.80 mmol) was added in one portion. The reaction was further stirred for 10 min. The crude product was dried under stream of N2 and purified by reversed phase HPLC to give 480 mg (55%) of 3-4. HRMS (ES) 369.0348 (M+H) found, 369.0349 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=O)[NH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[S:22])[NH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)c1[nH]c(=O)c(Nc2ccncn2)cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c(=S)c(Nc2ccncn2)cc1Cl
Temperature: 110 °C

Procedure:
A vial was charged with 3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate (3, 0.35, 1.2 mmol) and pyridine (10 mL) was added. To the above mixture phosphorus pentasulfide (0.53 g, 2.4 mmol) was added and reaction was heated at 110° C. for 16 h. TLC showed presence of starting material and phosphorus pentasulfide (0.265 g, 1.2 mmol) was added again and heated the reaction to 115° C. for 24 h. The pyridine was removed under reduced pressure and water (20 mL) was added and extracted with 5% methanol in dichloromethane (100 mL). The organic layer was washed with sodium bicarbonate and brine and layer was concentrated to dryness to afford ethyl 3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxylate (4) as brownish yellow solid and used directly without further purification. Yield: 350 mg, crude; MS (ESI) m/z 310.94 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[N:25]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].C(N(CC)CC)C.[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)#[N:16]>O1CCCC1>[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Sc1ccccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 885.2 %

Procedure:
To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 mL) was added triethylamine (15.5 g) in an ice-water bath under N2. To this was added a solution of 4-cyanobenzoyl chloride (25.3 g) in tetrahydrofuran (80 mL) below 10° C. over 30 minutes. After 15 minutes, the bath was removed and the mixture was stirred overnight at ambient temperature. The mixture was concentrated in vacuo. The residue was partitioned between chloroform and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue (38 g) was triturated with isopropyl ether to give S-(2-pyridinyl) 4-cyanobenzenecarbothioate (325 g) as a pale brown solid.
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[NH:27][C:26](=[S:28])[NH:25][C@:24]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:19][C:18]=1[F:37]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[N:27]3[C:26]([S:28][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]3[CH:9]([CH3:11])[CH3:10])=[N:25][C@:24]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:19][C:18]=1[F:37]
Reactant: C[C@@]1(c2ccc(Cl)nc2)NC(=S)N[C@@H]1c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C(C)C)N2C(=N[C@@](C)(c3ccc(Cl)nc3)[C@H]2c2ccc(Cl)c(F)c2)S1
Yield: 76.5 %

Procedure:
Ethyl 2-chloro-4-methyl-3-oxopentanoate (1.36 g, 7.09 mmol) was added to an ethanol (20 ml) solution of the compound (1.94 g, 5.45 mmol) obtained in Step 11 above at room temperature and the resulting mixture was heated to reflux for 16 hours. The reaction mixture was returned to room temperature and the reaction solvent was evaporated under reduced pressure. The residue obtained was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (2.06 g, 76%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[CH:44][C:45]([S:48](F)(=[O:50])=[O:49])=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:47][N:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(F)c1ccc(F)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 28 h
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (2.5 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (220 mg) and 5-fluoropyridine-2-sulfonyl fluoride (120 mg) at room temperature, and the mixture was stirred at room temperature for 28 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as a pale-yellow oil (yield 69 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3=[C:20]4[C:14](=[C:15]5[N:24]([CH3:25])[CH:23]=[CH:22][C:21]([C:26](O)=[O:27])=[C:16]5[CH:17]=[CH:18]3)[C:13](=[O:29])[NH:12][C:11]4=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH2:46][NH2:47])[CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH:45]=1)[CH2:46][NH:47][C:26]([C:21]1[CH:22]=[CH:23][N:24]([CH3:25])[C:15]2[C:16]=1[CH:17]=[CH:18][C:19]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH:10]=[C:11]3[NH:12][C:13](=[O:29])[C:14]=2[C:20]=13)=[O:27]
Reactant: CN1C=CC(C(=O)O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: COc1ccc(F)cc1CN
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: CC(=O)N(C)C
Product: COc1ccc(F)cc1CNC(=O)C1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 8 %

Procedure:
A stock solution of Example 56d and N,N-diisopropylethylamine (0.15 M and 0.42 M in N,N-dimethylacetamide, respectively, 254 μL) and (5-fluoro-2-methoxyphenyl)-methanamine (0.4 M in N,N-dimethylacetamide, 115 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.22 M in N,N-dimethylacetamide, 254 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0016 g (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.39 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.24, 2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.05 (m, 4H), 6.87 (m, 2H), 6.56 (m, 2H), 4.49 (s, 2H), 4.07 (s, 3H), 4.61 (m, 2H), 3.85 (s, 3H). MS (APCI+) m/z 527.2 (M+H)+.