Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:33][C:34](Br)([F:36])[F:35].O>CN1C(=O)N(C)CC1>[CH3:25][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:34]([Br:33])([F:36])[F:35])=[CH:7][CH:6]=1)([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1)[CH3:26]
Reactant: FC(F)(Br)Br
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)Br)cc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 21.6 g of 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether and 13.9 g of potassium t-butoxide in 120 ml of DMI was added dropwise to a mixture of 80 g of dibromodifluoromethane and 50 ml of DMI with stirring for 30 minutes at 50° to 60° C., and the mixture was maintained at this temperature for 3 hours. The reaction mixture was poured into water and extracted with toluene. The toluene solution was washed with dilute hydrochloric acid and water in this order, and dried. Toluene was evaporated under reduced pressure to give 29.4 g of an oily residue. The oily residue was purified by column chromatography [silica gel: 600 g; eluent: toluene/hexane (1:1)] to give 12.4 g of the desired 3-phenoxybenzyl 2-(4-difluorobromomethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OC)(OC)OC>[CH3:20][O:17][C:16](=[O:18])[CH2:15][C:13]1[N:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[S:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)c1ccc(-c2nc(CC(=O)O)cs2)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)Cc1csc(-c2ccc(C(C)C)cc2)n1
Yield: 884.2 %

Procedure:
A solution of 6.9 g (26.4 mmol) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetic acid and 0.5 g of p-toluenesulfonic acid mono-hydrate (catalyst) in 70 ml of methanol and 5 ml of trimethyl orthoformate was heated at reflux for 5 hours. After neutralization with aqueous sodium bicarbonate solution, evaporation of the solvents, extraction of the residue with tert-butyl methyl ether, drying over anhydrous sodium sulfate and evaporation of the solvent, 6.4 g (88% of theory) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester were obtained as light brown oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].[H][H].[C:16]1([C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][O:18]1)=[O:17]>CN(C)C=O>[C:16]([C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:19][O:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)([OH:18])=[O:17]
Reactant: [H][H]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C1OCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1COc1ccc2ccccc2c1

Procedure:
To a stirred suspension of 9.6 g. (0.2 mole) of a 50% dispersion of sodium hydride in mineral oil in 60 ml. of dimethylformamide is added dropwise a solution of 28.8 g. (0.2 mole) of 2-naphthol in 100 ml. of dimethylformamide at such a rate that the temperature does not exceed 25° C. After hydrogen evolution is complete, 26.8 g. (0.2 mole) of phthalide in 100 ml. of dimethylformamide is added dropwise and the stirred mixture is heated under reflux for 2 hours. The solvent is distilled off and the residue is diluted with ice-water. The mixture is extracted with ether and then the aqueous portion is made acidic with 12 N hydrochloric acid. The crystalline precipitate is filtered and recrystallized from aqueous ethanol, using decolorizing carbon to give 2-(2-carboxybenzyloxy)naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=[O:25])=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[CH:39]=[CH2:40].O>CN(C=O)C>[CH3:32][CH:22]([C:8]1[N:7]([CH2:6][C:5]2[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:15]2[C:10]([C:9]=1[S:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[CH:11][C:12]([O:16][CH2:38][CH:39]=[CH2:40])=[CH:13][CH:14]=2)[C:23]([CH3:29])([CH3:28])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)c(SC(C)(C)C)c(C(C)C(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
500 mg. of methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate from Step C of Example 1 was dissolved in 5 mL of DMF and 20 mg of K2CO3 and 150 mg of allyl bromide were added. The reaction was stirred for 16 hrs. Water was added and the organic phase extracted with EtOAc (3×5 mL). The organic phase was dried with MgSO4 and evaporated to yield, after chromatography on silica gel (EtOAc:hexane 1:5), the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:21]3[CH:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1cccnc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole (150 mg, 0.6 mmol), 3-bromopyridine (0.6 ml, 0.6 mmol), dichlorobis(triphenyl-phosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 ml 0.071 mmol) in acetonitrile (5 ml) was heated at 80° C. to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].C(N(C(C)C)CC)(C)C.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>ClCCl>[CH3:4][O:3][CH2:2][O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1cccc(-c2ccc(C(=O)OC)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloromethylmethyl ether (0.24 ml) and diisopropylethylamine (0.74 ml) was added to a solution of methyl 3′-hydroxymethylbiphenyl-4-carboxylate (504 mg), which is the product of Reference example 15(a), in anhydrous dichloromethane (10 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to stand at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (467 mg) as colorless crystals.
Reaction SMILES: [NH2:1][NH2:2].[F:3][S:4]([F:11])=[C:5](Cl)[C:6]([F:9])([F:8])[F:7].O>CO.CCOCC>[F:3][S:4]([F:11])=[C:5]([NH:1][NH:2][C:5](=[S:4]([F:11])[F:3])[C:6]([F:9])([F:8])[F:7])[C:6]([F:9])([F:8])[F:7]
Reactant: FS(F)=C(Cl)C(F)(F)F
Reactant: NN
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: FS(F)=C(NNC(=S(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Hydrazine (0.67 g, 0.02 mole) in methanol (5 ml) was stirred in a dry ice-acetone bath while pentafluorothioacetyl chloride (1.8 g, 0.0088 mole) in ether (3 ml) was added dropwise. After 15 minutes at 0° C., the mixture was poured into water and the insoluble material (0.35 g, mp 271° C. dec) was removed. An additional 0.7 g, mp 270° C. dec was recovered by concentrating the ether solution. Total yield of N,N'-bis(pentafluorothioacetyl)hydrazine is 1.05 g (66%); 1H NMR (acetone-d6): 4.78 (pentuplet); IR (KBr): 3190 (NH), 1635 (C=O), 895°-825 (SF5).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1I.C1(C)C=CC=CC=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(F)c(I)c1C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Temperature: 60 °C
Yield: 81 %

Procedure:
A 20 mL vial was charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile, (0.315 g, 1.00 mmol), Pd(PPh3)2Cl2 (0.014 g, 0.020 mmol) and CuI (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1.500 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1.100 mmol) was added dropwise via syringe and the septum was replaced by a PTFE-faced crimp top. The mixture was stirred in a heating block at 60° C. Upon cooling the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed (satd NH4Cl, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.231 g, 81% yield) as a light orange oil: 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=8.7, 5.0, 0.6 Hz, 1H), 7.39 (ddd, J=8.6, 7.8, 0.5 Hz, 1H), 0.28 (s, 9H); MS (GCMS EI) m/z 285 ([M]+, 15%), 270 ([M-CH3]+, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](=O)[C:28](OC)=[O:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]3[C:28](=[O:29])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: CCOc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (381 mg, 2.02 mmol) and methyl 2-(6-ethoxy-1H-indol-3-yl)oxoacetate (500 mg, 2.02 mmol) in DMF (17 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (2.0 mL, 2.0 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional potassium tert-butoxide (1.0 M, 4.1 mL, 4.1 mmol) was added. The resulting dark purple solution was heated up to 70° C. over night. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (12 mL) and poured into EtOAc (500 mL). The organic layer was separated, dried (MgSO4), and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (200 mg, 26%) as a red solid, mp 212–215° C. 1H NMR (CDCl3) δ 8.44 (s, 1H), 7.88 (s, 1H), 7.68 (m, 1H), 7.60 (s, 1H), 7.00 (m, 2H), 6.92 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 6.32 (s, 2H), 3.92 (q, J=6.5 Hz, 2H), 3.72 (s, 3H), 1.38 (t, J=6.5 Hz, 3H). MS (ESI, Negative Mode): m/z=384 [C23H19N3O3−H]−
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:25])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-fluorophenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 22.7 mg (25%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.78 (s, 1H), 9.55-9.54 (m, 1H), 9.00-8.99 (m, 1H), 8.58-8.53 (m, 1H), 8.43 (s, 1H), 7.94-7.39 (m, 11H), 4.65-4.63 (t, J=3 Hz, 2H), 3.89 (s, 2H), 2.63-2.59 (m, 2H). MS (ES, m/z): 612 [M+H]+.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1.O>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:6]2[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][CH:7]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: CNCC(O)c1ccc(Br)cc1
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O
Product: CNCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to a stirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg, 0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred at room temperature for 17 hours. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) and saturated NaHCO3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product. LC/MS: (PS-B3) Rt 3.58 [M÷H]+ 324.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Yield: 69.2 %

Procedure:
A solution of acryloyl chloride (0.017 mL, 0.21 mmol) in CH2Cl2 (0.6 mL) was added to a mixture of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 65, 87 mg, 0.19 mmol) and DIPEA (0.063 mL, 0.38 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was then stirred at 0° C. for 4 h. (during this time a further 0.5 eq acryloyl chloride was added). The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3, then with water, and then dried (MgSO4). Purification by FCC, eluting with 0-6% methanolic ammonia in CH2Cl2 gave the title compound (67 mg, 69%) as a yellow solid; 1H NMR: (102° C.) 2.30 (3H, s), 2.56-2.59 (4H, m), 2.93-2.96 (4H, m), 3.78 (3H, s), 5.67-5.7 (1H, m), 6.16 (1H, d), 6.44-6.51 (1H, m), 6.95 (1H, s), 7.11 (1H, t), 7.35 (1H, t), 8.20 (1H, s), 8.32 (1H, d), 8.66 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.91 (1H, s), 8.96 (1H, br s); m/z: ES+ MH+ 510.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.ClCCl.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>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Brc1cccc(NCc2cccnc2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
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: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc(NCc3cccnc3)c2)cc1
Temperature: 25 °C

Procedure:
A solution of N-(3-bromophenyl)pyridin-3-ylmethylamine (364 mg, 1.38 mmol), 4-cyanophenylboronic acid (305 mg, 2.08 mmol), sodium carbonate (2.15 ml of a 2M aqueous solution, 4.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol), under a nitrogen atmosphere was refluxed in dioxane (15 ml) for 6 h, then cooled to room temperature. The mixture was diluted with dichloromethane (70 ml) and water (15 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated to a brown solid. The solid was purified by radial chromatography eluting with 2 to 4% methanol/dichloromethane to afforded the title compound. MS calcd. 285.3; MS (M+1) 286.3.
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]([CH2:27][C:28]([O:30]C)=O)[NH2:26])[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:27][C:28](=[O:30])[NH:10][C:9](=[O:8])[NH:26]2)[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cccc(N(N)CC(=O)OC)c1
Reactant: N#C[O-]
Agent: NN
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.2 ml, 15.5 mmol) was added to a suspension of sodium cyanate (1.17 g, 18.0 mmol) and hydrazine (Intermediate 47 1.30 g, 5.15 mmol) in toluene (17 ml) at room temperature and stirred for 2 h. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate and washed with sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to afford the urea intermediate as a brown oil. A portion of this crude urea (0.65 g, 2.2 mmol) was taken up in methanol (10 ml) and treated with sodium methoxide (0.48 g, 8.8 mmol) at room temperature for 2 h. The reaction was quenched (pH 6.5 buffer), extracted with ethyl acetate, washed with water followed by brine, dried (Na2SO4) and concentrated to afford a red oil which was triturated with ether to afford a pale brown solid (105 mg, 18%), m.p. 100°-105°.
Reaction SMILES: Br[CH:2]([CH2:11][CH3:12])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:20][C:2]=1[CH2:11][CH3:12])[CH3:9]
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)C(Br)CC
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1CC
Yield: 19.6 %

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from ethyl 4-bromo-3-oxo-hexanoate (3.32 g, 14 mmol) and 6.79 g (56 mmol) of benzamide to give 710 mg of Intermediate 1B: TLC Rf=0.69 (2/1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ7.98 (m, 2H), 7.41 (m, 3H), 4.18 (q, 2H, J=6.9), 3.57 (s, 2H), 2.72 (q, 2H, J=7.5), 1.29-1.24 low resolution MS (ES+)m/e 260.1 (MH+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:15][C:16]([F:34])([F:33])[C:17]([N:19]([CH2:26][P:27]([O:31]Cl)([O:29]Cl)=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18].[CH2:35]([SH:37])[CH3:36]>CCOCC>[F:15][C:16]([F:34])([F:33])[C:17]([N:19]([CH:26]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[P:27]([OH:31])([O:29][S:37][CH2:35][CH3:36])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18]
Reactant: CCS
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(Oc1ccccc1)P(=O)(O)OSCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
A solution of phenol (2.68 g, 0.0285 mole) and triethylamine (3.97 ml, 0.0285 mole) in 50 ml. of ether was added to a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (9.9 g, 0.03 mole) in 175 ml. of ether at 0° C. After three hours, the reaction mixture was filtered and the cooled (0° C.) filtrate was treated with a solution of ethanethiol (2.13 ml, 0.0285 mole) and triethylamine (3.97 ml, 0.0285 mole) in 50 ml. of ether. After stirring at 25° C. overnight, the solution was filtered and the filtrate was washed with 1.5% hydrochloric acid, 1.5% ammonium hydroxide and saturated sodium chloride solution. Concentration in vacuo afforded an oil which was chromatographed on silica gel eluting with ethyl acetate/cyclohexane (1:1) to yield ethyl N-trifluoroacetyl-N-(phenoxy(ethylthio)phosphonomethyl)glycinate (1.5 g) as a clear oil, ND25 =1.4969.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([OH:17])[CH:15]=[CH2:16].C(OOC(C)(C)C)(C)(C)C>>[OH:17][CH2:14][CH2:15][CH2:16][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]1=[O:13]
Reactant: O=C1CCCCCCCCCCC1
Reactant: C=CCO
Agent: CC(C)(C)OOC(C)(C)C
Product: O=C1CCCCCCCCCCC1CCCO

Procedure:
From a double-walled vessel made of glass, whose temperature is thermostatically controlled at 100° C. and which is fitted with a magnetic stirrer and serves as the storage container for the cyclododecanone, 400 g/h are pumped to a mixing column which is kept at a temperature of 100° C. 21.4 g/h of a mixture of allyl alcohol (12.2 g/h) and di-tert-butyl peroxide (9.2 g/h) are continuously metered into the feedline of the mixing column.