Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Br)cc3)cc2)CCOCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccc(-c4cccs4)cc3)cc2)CCOCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of 4-[4-(4-bromophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid (1.10 g, 2.42 mmol) of in N,N-dimethylformamide (15 mL) was added tetrakis(triphenylphosphine)palladium(O) (108 mg), 2-thiophene boronic acid (857 mg, 6.70 mmol), followed by 2M aqueous sodium carbonate (2.7 mL, 5.4 mmol). The reaction was heated to reflux for 10 hours, cooled to room temperature, and the mixture partitioned between methylene chloride (100 mL) and 1N aqueous hydrochloric acid (20 mL). The aqueous layer was back extracted with methylene chloride (100 mL), and the combined organic layers dried (MgSO4), the residue chromatographed over 100 g of silica gel (eluted with methylene chloride to 10% methanol/methylene chloride), and the resulting foam crystallized from the minimum amount of methylene chloride/hexanes to afford 4-[4-(4-(thiophen-2-yl)phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid (1.04 g, 94%). mp 181.2-193.3° C.; IR (KBr) 3432 (br), 1718.9 cm-1 ; 1H NMR (DMSO-d6) δ 1.67 (ddd, J=13.8, 9.4, 4.0 Hz, 2H), 1.95 (dm, J=13.8 Hz, 2H), 3.47 (mc, 2H), 3.67 (mc, 2H), 3.68 (s, 2H), 7.14 (dd, J=4.9, 3.6 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.9 Hz, 2H), 7.50 (dd, J=3.6, 1.2 Hz, 1H), 7.54 (dd, J=4.9, 1.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 12.80 (s, 1H); 13CNMR (DMSO-d6) δ 32.92 (t), 42.25 (s), 61.73 (t), 63.26 (t), 117.82 (d), 123.75 (d), 125.66 (d), 127.39 (d), 128.50 (d), 130.08 (d), 130.74 (s), 134.90 (s), 142.42 (s), 154.13 (s), 161.33 (s), 174.39 (s); FABHRMS Calcd. for C23H24S2O6 (M+ +H): 459.0936. Found: 459.0936. Anal. Calcd. for C23H23S2O6 : C, 60.24; H, 4.83. Found: C, 60.57; H, 4.90.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[CH:18](N1CCCCC1)=[O:19].Cl>O1CCCC1.O>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH:18]=[O:19])=[C:12]([F:17])[CH:11]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
55 ml (0.11 mmol) of 2 M lithium diisopropylamide are added with stirring at −70° C. to a solution of 19.3 g (0.1 mmol) of 1-bromo-3,5-difluorobenzene in 120 ml of dried tetrahydrofuran. After 30 minutes, N-formylpiperidine is added dropwise at this temperature. The mixture is allowed to warm to 0° C. At about 0° C., the reaction mixture is poured into cold water, acidified using 10% HCl and extracted twice with methyl tert-butyl ether. The combined organic phases are washed with water, dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure. The residue is filtered through SiO2 (heptane/dichloromethane 1:1), (yield: 17.6 g, 78%).
Reaction SMILES: [I-].[K+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19]Cl)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:10]=2[CH:28]=1)([O-:5])=[O:4].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>O1CCCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][NH:32][CH:29]4[CH2:31][CH2:30]4)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:10]=2[CH:28]=1)([O-:5])=[O:4]
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-nitro 1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: CCN(CC)CC.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[CH:9]1>[Pd].C(O)=O>[NH:8]1[C:16]2=[N:15][CH:14]=[CH:13][CH:12]=[C:11]2[CH2:10][CH2:9]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: c1cnc2c(c1)CCN2
Temperature: 25 °C

Procedure:
98% Formic acid (37.5 mL, 0.97 mol) was added to a stirred and cooled (ice bath) neat Et3N (150 mL, 1.08 mol). A two-phase system, which was formed, was then added to a mixture of 7-azaindole (50.0 g, 0.424 mol), formic acid (750 mL), and 10% palladium on activated carbon (26.75 g, Degussa type), and stirred at 80° C. for 4 d. The mixture was cooled to r.t., the catalyst was filtered off and washed with formic acid (100 mL). The filtrate and washings were combined and concentrated in vacuum. The residual liquid was cooled (ice bath) and basified to pH 13 by slow addition of 50% aqueous NaOH (total of about 500 mL). Then, the mixture was refluxed for 2 h until TLC showed completion. Ice was added in amount sufficient to lower the temperature of the mixture to 20° C. The two-phase system was then extracted with AcOEt (5×500 mL). Combined extracts were washed with brine, dried MgSO4, and concentrated in vacuum. The residual brown solid was separated by means of SGC with AcOEt:MeOH as eluent to afford recovered 1 (12.57 g, 25%) and desired 2 (36.05 g, 71%). 1H NMR (400 MHz, CDCl3) δ 3.05 (t, J=8.4 Hz, 2H), 3.60 (t, J=8.4 Hz, 2H), 4.52 (bs, 1H), 6.49 (dd, J=7.0, 5.3 Hz, 1H), 7.23 (dq, J=7.0, 1.3 Hz, 1H), 7.81 (ddt, J=5.3, 1.3, 1.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([NH:20][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Nc1ccnc(Cl)c1
Product: Cc1ccc2ccnc(Nc3ccnc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=271.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-chloro-4-aminopyridine.
Reaction SMILES: IC1SC(NC(=O)C)=NC=1C.[CH3:12][C:13]1[N:14]=[C:15]([NH:30][C:31](=[O:33])[CH3:32])[S:16][C:17]=1[C:18]1[S:19][C:20](S(NCC#C)(=O)=O)=[CH:21][CH:22]=1.C([Sn](CCCC)(CCCC)C1SC=CC=1)CCC>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:13]1[N:14]=[C:15]([NH:30][C:31](=[O:33])[CH3:32])[S:16][C:17]=1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)Nc1nc(C)c(I)s1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2cccs2)s1
Temperature: 100 °C

Procedure:
N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (2 g; 7.09 mmol; 1 eq.) and Pd(dppf)Cl2 (0.52 g; 0.71 mmol; 0.10 eq.) are dissolved in DMF (35 ml). 2-(Tributylstannyl)thiophene (2.68 ml; 8.44 mmol; 1.19 eq.) is added. The reaction mixture is flushed with argon and heated at 100° C. for 1 h 30. Solvents are evaporated and the crude mixture is dissolved in EtOAc (100 ml), washed with water (3×100 ml). The aqueous phase are combined and extracted with EtOAc (2×50 ml). Combined organic phases is washed with brine and dried over MgSO4. After evaporation of the solvents, the crude product is purified by preparative HPLC, affording N-[4-methyl-5-(2-thienyl)-1,3-thiazol-2-yl]acetamide as white-off powder (1.24 g; 73.5%). 1H NMR (DMSO-d6) δ 2.16 (s, 3H), 2.42 (s, 3H), 7.15 (dd, J=3.8, 5.3 Hz, 1H), 7.20 (dd, J=1.1, 3.8 Hz, 1H), 7.60 (dd, J=1.1, 5.3 Hz, 1H), 12.19 (s, 1H). M− (ESI): 237.01; M+ (ESI): 239.01. HPLC, Rt: 3.01 min (purity: 98.7%).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCOc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
In a 1 L jacketed flask under a nitrogen atmosphere is added 60 g (0.2425 mols) of p-dodecyloxyaniline, 650 mL of CH2Cl2 and 56.6 g of pyridine (0.716 mols) and the resulting solution is cooled to 0° C. Maintaining an internal temperature below 5° C., 46.3 g (0.339 mols) of ethyl chlorooxoacetate is then added dropwise over a period of one hour. After the addition is complete, the internal temperature is maintained at 10° C. overnight. To the resultant reaction mixture is added rapidly 400 mL of 1N HCl and the resultant mixture is allowed to warm to RT. The reaction mixture is stirred for one hour than the organic phase separated. The organic phase is dried over anhydrous sodium sulphate and isolubles removed by filtration. The volatiles are removed in vacuo and the residue is recrystallized from ethanol (250 mL). The solid is washed twice with ethanol (50 mL) at 0° C. to give 64.1 g of a white solid, mp. 70.5–72° C. The NMR, MS and IR spectra are consistent with the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[CH:3]=1)=[O:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (82 mg, 0.4 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (10.8 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (66.4 mg, 0.79 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. The mixture was evaporated, DCM/MeOH (1:1) was added, and the contents pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes, it was sonicated, and the solids that precipitated were filtered. Acetonitrile was added, solids that precipitated were filtered, and further washed with acetonitrile/ether (2:8) and dried to afford the title compound as an off-white solid (84 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.48 (t, J=4.93 Hz, 1H) 8.31 (s, 1H) 8.26 (s, 1H) 8.04 (s, 1H) 8.03 (s, 1H) 7.81 (d, J=1.01 Hz, 1H) 5.90 (s, 1H) 5.06 (quin, J=6.57 Hz, 1H) 4.39 (s, 1H) 4.38 (s, 1H) 3.90 (s, 3H) 2.23 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.48 (s, 3H); LC-MS (ES) m/z=419.0
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:5]1
Reactant: COC(=O)C1CNCC(C)C1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(C)CN(Cc2ccccc2F)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (8 mL) and acetic acid (8 drops) was added to methyl 5-methylpiperidine-3-carboxylate (300 mg, 1.9 mmol) and 2-fluorobenzaldehyde (3.8 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (1.6 g, 7.6 mmol) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:22][N:23](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:24].F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.CNC>CN(C=O)C.O>[CH3:22][N:23]([CH3:24])[C:8]([C:5]1[C:4](=[O:11])[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[C:2]([CH3:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cnc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A mixture of 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylic acid (0.21 g, 0.7 mmol), HATU (0.266 g, 0.7 mmol) and Et3N (0.293 g, 2.9 mmol) in DMF (2 ml) was reacted with dimethylamine HCl. After 2 h, the reaction mixture was diluted with water and extracted with ethyl acetate (3×5 ml). The organic phase was dried (MgSO4), filtered and evaporated. No further purification was performed.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.[C:20]([C:28]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:13]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]3[C:29](=[CH:33][CH:34]=[C:35]([Br:37])[CH:36]=3)[C:30]2=[O:31])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCCC(O)CNCc1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzoic acid methyl ester hydrochloride and 2-benzoyl-4-bromobenzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:57])[CH2:47][N:48]1[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[OH:57][CH:46]([CH2:47][N:48]1[CH2:49][C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56]1)[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccccn2)c1
Reactant: NCC(O)CN1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1Cc2ccccc2C1)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(pyridin-2-yl)benzoic acid (60 mg, 0.30 mmol) in DCM (8 mL) was added EDCI (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol), Et3N (61 mg, 0.6 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (86 mg, 0.45 mmol). The mixture was stirred at 25° C. for 16 h, washed with water and extracted with DCM. The combined organic extracts were concentrated, and the residue was purified by preparative HPLC purification. (30 mg, 27%) MS (ESI+) e/z: 374.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.65 (d, J=4.8 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.96-7.92 (m, 3H), 7.62 (dd, J=7.2 Hz, 1H), 7.40-7.35 (m, 6H), 4.70 (s, 4H), 4.29 (br.s, 1H), 3.63-3.30 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 10-3 (4.36 g, 22 mmol) in dimethylsulfoxide (DMSO; 30 mL) were added morpholine (2.5 g, 1.3 eq) and potassium carbonate (3.98 g, 1.3 eq). The reaction mixture was heated at 80° C. during 1 h, then cooled down to room temperature, poured into 300 mL of water and the resulting yellow solid was filtered off, washed with a bit of water then petroleum ether, to afford 5.8 g (98% yield) of 2-morpholin-4-yl-5-nitro-benzoic acid methyl ester 10-4; m/z=267 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=12.[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][NH:25][C:24](=[O:27])[CH2:23]1.CN(C=O)C.[H-].[Na+]>O>[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][N:25]([CH2:2][C:3]2[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5][N:6]3[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=23)[C:24](=[O:27])[CH2:23]1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: Cc1cnc2c(CCl)c(-c3ccccc3)nn2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(CN3CC(C=C(F)F)CC3=O)c(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The above mentioned solution of intermediate x146 is added to a solution containing 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.64 mmol, 1.1 eq, 0.356 g), 6 ml of dry DMF and sodium hydride (60% dispersion in oil, 2.64 mmol, 1.1 eq, 0.1 g) that have been stirred at room temperature for 0.5 hour. The resulting mixture is heated up at 80° C. for 1 hour. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is crystallized in AcOEt to afford 0.443 g of 4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one 211.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]1COCC1>>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: C1CCOC1
Reactant: O=C1CCCc2ccccc21
Product: C=C1CCc2ccccc2C1=O

Procedure:
To a solution of 1-tetralone (164.5 g) in about 400 ml THF was added, in four separate portions, TAMA (243 g) and trioxymethylene (99 g) over 31/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and portioned between Et2O and water, the layers separated and the aqueous layer extracted twice with Et2O. The combined Et2O layers are exhaustively washed with water, NaHCO3 and then with brine, dried (MgSO4) concentrated in vacuo to yield an oil which is flash chromatographed on silica gel using CH2Cl2 in several runs of 10-20 g per run. Fractions containing the fast moving material are combined, concentrated in vacuo to obtain the desired 2-methylene-1-tetralone.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[CH3:12][O:11][C:10]1[C:2]([CH:21]=[O:22])=[CH:3][C:4]2[O:8][CH2:7][CH2:6][C:5]=2[CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1Br)OCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)OCC2
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 6-bromo-5-methoxy-2,3-dihydrobenzofuran (9.20 g, 40.35 mmol) in THF (50 mL) was dropwise added n-Butyl lithium (24.00 mL, 38.40 mmol) at -78° C. After stirring for 30 min. DMF (5.00 mL, 60.53 mmol) was added and the mixture was allowed to stir at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Flash chromatography (1:1 ether/hexane) of the residue afforded 5.42 g (76%) of the title compound as a yellow solid: 1H NMR (250 MHz, CDCl3) d 10.32 (s, 1 H), 6.90 (s, 1 H), 6.82 (s, 1 H), 4.57 (t, 2 H), 3.91 (s, 3 H), 3.25 (t, 2 H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN([CH:36]=[O:37])C>C1COCC1>[Si:20]([O:23][CH2:24][CH2:25][C:26]1[C:27]([F:32])=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:36]=[O:37])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (11.0 g) in anhydrous THF (200 mL) was cooled to −78° and treated with butyllithium (37.5 mL), added steadily over 5 minutes via a syringe. The solution was stirred at −78° for 15 minutes and then treated with a solution of tert-butyl(2-fluorophenethoxy)dimethylsilane [Aromatic Intermediate 5, step a] (9.9 g) in THF (25 mL), added dropwise over 15 minutes. The solution that was stirred at −78° for 2 hours, then treated with a solution of DMF (9.0 mL) in THF (25 mL), added dropwise over 10 minutes. The solution was stirred at −78° for 1 hour, then the cooling bath was removed and the solution was allowed to warm to room temperature overnight. The reaction mixture was poured into aqueous HCl (0.5M) and extracted three times with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the titled compound. Yield 10.1 g.