Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH:7]([OH:15])[CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])#[N:2].OO.[ClH:22]>CCOCC>[C:1]([C:3]1[CH:19]=[C:18]([Cl:22])[CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH:7]([OH:15])[CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])#[N:2]
Reactant: Cl
Reactant: CC(C)(CO)NCC(O)COc1ccccc1C#N
Agent: OO
Solvent: CCOCC
Product: CC(C)(CO)NCC(O)COc1ccc(Cl)cc1C#N
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
9.7 gm (about 0.037 mol) of 1-(2'-cyano-phenoxy)-2-hydroxy-3-[(1",1"-dimethyl-2"-hydroxy-ethyl)-amino]-propane, prepared as in Example 1, were dissolved in 75 ml of concentrated hydrochloric acid, the solution was heated to 45°C., and then 4.7 gm of an aqueous 30% hydrogen peroxide solution (about 0.038 H2 02) were added dropwise. A strong exothermic reaction ensued, and the temperature of the reaction mixture was kept at 65°C. by exterior cooling. After all of the peroxide had been added, the reaction solution was stirred for 30 minutes at 60°-65°C. and subsequently evaporated to dryness in vacuo. The residue was dissolved in water, the resulting solution was extracted twice with ether, and the aqueous phase was made alkaline with 2N sodium hydroxide. The oily precipitate formed thereby was taken up in ether, and the resulting solution was washed with water, dried and evaporated, leaving 9.3 gm of a solid residue which was recrystallized twice from ethyl acetate by addition of petroleum ether (40°-60°C.). 6.6 gm of the compound of the formula ##EQU10## having a melting point of 102°-103°C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][C:20]=3[S:21][C:22]=2[N:23]([CH3:25])[CH3:24])=[O:17])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([O-])=O.[BH4-].[Na+].O.[OH-].[Na+]>CCO.CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:26][C:20]=3[S:21][C:22]=2[N:23]([CH3:25])[CH3:24])=[O:17])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(CN2CCCC2)c(N)c1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
The 492 mg (0.955 mmol) of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-nitro-4-(1-pyrrolidinylmethyl)phenyl ketone (Part D, above) was dissolved in 21 mL of an EtOH/MeOH mixture (5:2 ratio). To the reaction mixture was added 1.07 g (4.77 mmol) of stannous chloride dihydrate. The reaction mixture was heated to 75° C. and to the solution was added 18.1 mg of sodium borohydride dissolved in 10 mL of EtOH/MeOH mixture (7:3 ratio). The solution was added dropwise via syringe over 25 min. The reaction mixture was stirred at 75° C. for 1.5 h. The reaction was then allowed to cool to room temperature. and was then poured into 20 mL of chilled (0° C.) water. The mixture was neutralized by adding 4 mL of 2 N NaOH solution and then concentrated under reduced pressure to a volume of 30 mL. This mixture was extracted with EtOAc (4×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 451 mg (97% crude yield) as a orange foam.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][C@@H:6]([CH2:19][O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)C.FC(F)(F)S(O)(=O)=O>C1COCC1.O>[OH:3][CH2:4][CH2:5][C@@H:6]([CH2:19][O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CC(OCC)OCC)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 22 °C
Reaction time: 2 h

Procedure:
The product of Example 30, step d) (3.0 kg) was slurried in THF (46 L) at 20° C. A solution of trifluoromethanesulfonic acid (2.25 kg) in 2.25 kg of water (prepared by slowly adding the acid to cold water) was added and the reaction mixture was stirred at 22° C. for 2 hours. The reaction mixture was cooled to 15° C. and quenched with a solution of NaHCO3 (1.5 kg) in water (5.3 kg). Borane t-butylamine complex (powder, 340 g) was added in four portions and then the reaction temperature was increased to 35° C. and stirred for 12 hours. The reaction mixture was added to a solution of 320 g of concentrated HCl (37% aq.) in 115 kg of tap water at 5° C. This mixture was stirred for 30 minutes and the resulting precipitate was filtered and washed with acetonitrile (15 kg). The solids were reprecipitated once or twice from acetone (35 kg). A final precipitation was accomplished by dissolving the product in THF (24 kg) at 65° C., adding water (1.3 kg), cooling to 30° C. and then adding methylene chloride (105 kg). The resulting slurry was cooled to 10° C. and the precipitate was filtered to provide the desired product.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:12][C:8]1[C:9]([Cl:11])=[CH:10][C:4]2[NH:3][C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)=[N:6][C:5]=2[CH:7]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc3cc(Cl)c(Cl)cc3[nH]2)CC1

Procedure:
The benzoimidazole from step (b) above (0.110 g, 0.5 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.231 g, 1 mmol, Maybridge) reacted under the conditions Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=O)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][C:17]1[C:18]([O:32][CH3:33])=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:21]1[CH:20]=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([O:32][CH3:33])=[C:17]([NH:16][C:13]([C:10]2[S:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[CH:11]=2)=[O:15])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(O)c1cc2c([N+](=O)[O-])cccc2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3c([N+](=O)[O-])cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.4 %

Procedure:
4-Nitro-benzo[b]thiophene-2-carboxylic acid (369 mg, 1.65 mmol) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (500 mg, 1.84 mmol) were dissolved in 25 mL DMF and stirred at room temperature. After about 10 min, EDC (317 mg, 1.65 mmol) and HOBt (224 mg, 1.65 mmol) were added and the brown solution was stirred at room temperature 12 h. After stirring 12 h, the reaction was partitioned between EtOAc (150 mL) and water (50 mL). The layers were separated and the organic portion was washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford a brown solid. Column chromatography on silica gel afforded 4-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a pale yellow solid (200 mg, 25%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:16](=[O:18])[CH3:17])[C:6]1=[O:19].[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:16](=[O:18])[CH3:17])[C:6]1=[O:19]
Reactant: [H][H]
Reactant: COCCn1cc(-c2ccccc2)n(C(C)=O)c1=O
Agent: [Pd]
Solvent: CCO
Product: COCCN1CC(c2ccccc2)N(C(C)=O)C1=O

Procedure:
Approximately 3.9 g. of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one and 400 mg. of 10% palladium on carbon in 30 ml. of ethanol is hydrogenated in the Parr Shaker apparatus at 30 psig of hydrogen. After one hour the catalyst is filtered and washed with 50 ml. of ethanol. The combined filtrate is concentrated to yield the title compounds as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]([F:23])([F:22])[F:21])=[C:13]([S:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24]>>[ClH:24].[CH2:18]([S:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22])[CH2:9][NH:8][CH2:16]2)[CH3:19]
Reactant: CCSc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCSc1cc2c(cc1C(F)(F)F)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-ethylsulfanyl-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Yellow solid. MS (m/e): 284.3 ([M+H]+, 100%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])(=[O:9])=[O:8].C([Li])CCC.[CH3:31][C:32]([CH3:34])=[O:33].FC(F)(F)C(O)=O>C1COCC1>[OH:33][C:32]([CH3:34])([CH3:31])[CH:10]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])[S:7](=[O:8])(=[O:9])[NH2:6]
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(C(=O)O)c2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cccc(C(=O)O)c1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 3-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid (4.1 g) in THF (50 ml) was added dropwise, at −78° C., butyllithium (1.6 M, 25 ml). The mixture was stirred for 10 min. Subsequently, acetone (4.5 ml) was added and the mixture was stirred at −78° C. for a further 30 min. The reaction mixture was then admixed with trifluoroacetic acid (4 ml) and concentrated. The residue was suspended in dichloromethane and trifluoroacetic acid (10 ml) admixed. After 2 h, water was added and the mixture was filtered. The aqueous phase was removed and freeze-dried. The residue was purified by means of preparative HPLC. This gave the product (1.1 g) with a molecular weight of 273.3 g/mol (C11H15NO5S).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:37])([F:36])[F:35])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:36])([F:35])[F:37])[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:153-155° C.; 1H NMR (300 MHz, CDCl3) δ: 10.34 (1 H, s), 8.36 (1 H, s), 8.24-8.27 (1 H, d, J=8.1 Hz), 8.03 (1 H, s), 7.82-7.85 (1 H, d, J=8.1 Hz), 7.48 (1 H, s), 7.41-7.44 (1 H, d, J=8.7 Hz), 7.34-7.37 (2 H, t, J=9.3 and 8.7 Hz), 6.80 (1 H, s), 6.61-6.64 (1 H, d, J=9.6 Hz), 5.57-5.59 (1 H, d, J=6.0 Hz), 4.22-4.29 (1 H, m), 2.45-2.48 (2 H, m), 2.28 (3 H, s), 1.76-2.01 (4 H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0817.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[F:5][C:6]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[C:25]([F:28])([F:27])[F:26])[N:17]=[C:16]([NH:29][CH3:30])[N:15]=2)[CH:11]=[C:10](F)[C:7]=1[C:8]#[N:9]>CO>[F:5][C:6]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[C:25]([F:28])([F:27])[F:26])[N:17]=[C:16]([NH:29][CH3:30])[N:15]=2)[CH:11]=[C:10]([O:2][CH3:1])[C:7]=1[C:8]#[N:9]
Reactant: C[O-]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium methoxide was made from 65 mg of sodium dissolved in 2.8 mL of CH3OH. From that solution 0.4 mL was added to a predissolved solution of 2,6-difluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (127 mg, 0.331 mmol) in CH3OH (3 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated, then diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The organic was combined, dried over MgSO4, filtered and concentrated to afford the crude title compound (131 mg). LC-MS (ES) m/z=396 [M+H]+.
Reaction SMILES: C(C[O:4][C:5](=O)[CH:6]=[CH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)#N.CO.O.[NH2:21][NH2:22]>O>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=[C:8]1[CH:7]=[CH:6][C:5]([NH:21][NH2:22])=[O:4]
Reactant: N#CCOC(=O)C=Cc1cc2ccccc2o1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C=Cc1cc2ccccc2o1
Yield: 90.1 %

Procedure:
187 g of the β-(2-benzofuryl)acrylic acid cyanomethyl ester were added to 2 liters of methanol, and to the mixture, with stirring, were added 76.8 g of hydrazine hydrate, and then the resulting mixture was refluxed by heating for 30 minutes. After the reaction, 2 liters of water were added to cool the reaction product, and the deposited crystals were filtered by a suction filter, then washed, and then recrystallized from methanol, thereby obtaining 150 g of β-(2-benzofuryl)acrylic acid hydrazide having a melting point between 173° C. and 174° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:42])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:41]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:18]=[CH:17][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:42])=[CH:21][CH:20]=4)=[N:41][C:27]2=3)[CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3)ncc21
Reaction time: 1 h
Yield: 760.5 %

Procedure:
A mixture of 0.075 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.048 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-benzamide (I-14).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].O1CCO[CH2:18][CH2:17]1>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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:17]#[CH:18])[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C#Cc1cc(C(=O)OC)c(N)cc1C(C)C
Yield: 72 %

Procedure:
A solution of 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester (1.5 g, 4.7 mmol), Bu3SnCCH (1.5 mL, 5.17 mmol) and (Ph3P)4Pd (271.6 mg, 0.235 mmol) in dioxane (80 mL) was heated at 120° C. for 1.5 h. The solvent was removed in vacuo. The residue was purified by two successive flash chromatographies (160 g silica gel, hexanes→EtOAc:hexanes (3:7 to 1:1), then (50 g silica gel, hexanes→EtOAc:hexanes (1:9)) to provide 2-amino-5-ethynyl-4-isopropyl-benzoic acid methyl ester (738 mg, 72%) as a yellowish oil. API-ES: m/z 218 [M+H]+, rt 5.45 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3CC3)[CH2:8][C:6]=2[N:7]=1.C=O.Cl.ClC1N=C(N2CCOC[C@@H]2C)C2CCNCC=2N=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:12][CH2:11][N:9]([CH3:10])[CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Agent: C=O
Agent: C[C@H]1COCCN1c1nc(Cl)nc2c1CCNC2
Agent: Cl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C)C2
Yield: 78 %

Procedure:
Method as described for intermediate 8 using formaldehyde (37% solution in water) and (S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride as starting materials. The mixture was partitioned between saturated NaHCO3 solution and DCM. The organic layer was recovered, dried over MgSO4, filtered and reduced in vacuo, yielding the title compound (2.11 g, 7.47 mmol, 78%).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])[O-:3].[K+].C[Si](C)(C)O[Si](C)(C)C.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[C:18](F)=[O:19]>>[C:21]([C:17]([C:18]([O:3][Si:2]([CH3:5])([CH3:4])[CH3:1])=[O:19])([F:25])[F:16])([F:24])([F:23])[F:22]
Reactant: C[Si](C)(C)[O-]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: C[Si](C)(C)OC(=O)C(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
A 200 mL Hastelloy® pressure vessel was heated for 6 hr at 150° C. under a nitrogen purge. At room temperature, the vessel was charged with potassium trimethylsilanolate (0.65 g, 5.1 mmol) and hexamethyldisiloxane (81 g, 0.50 tool) and then sealed, cooled and evacuated. Pentafluoropropionyl fluoride (47.4 g, 0.27 mol) was transferred from a cycinder to the pressure vessel. Once sealed, it was heated at 125° C. (barricade). The pressure rapidly increased to 1.79 MPa and then dropped to 0.62 MPa during a 1.5 hr period. The pressure vessel was heated for a total of 24 hr. The cooled pressure vessel was pressurized with nitrogen and the contents were transferred to a dried bottle. The crude product was transferred under vacuum and subsequently fractionated by spinning band distillation to remove most of the trimethylsilyl fluoride. The remaining 100 g of colorless liquid was a mixture of three components: trimethylsilyl pentafluoropropionate (49.7%) , hexamethyldisiloxane (42.6%) , and trimethylsilyl fluoride (7.6%) as determined by GC analysis, 1H and 19F NMR analyses. 19F NMR(CDCl3): -83.4 (s, CF3), -122.28 (s, CF2), -158.2 (m, SiF). 1H NMR: 0.40 (s, CO2SiMe3), 0.22 (d, Me3SiF), and 0.06 (s, Me6Si2O). GC/MS analysis of a previously prepared sample of CF3CF2CO2SiMe3 featured a component with m/z@220.989868 (calcd forC5H6F5SiO2 =221.005722), consistent with M--CH3.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH2:4]1
Reactant: Clc1ccc(Br)nc1
Reactant: O=C1NC[C@@H](CCl)O1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1O[C@H](CCl)CN1c1ccc(Cl)cn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A mixture of (5S)-5-(chloromethyl)-1,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 4), 2-bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium tribenzylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2×) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volumes), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.44 g, 61%). Mass spectrum (ESI) 249.0 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3Br)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:18])[C:19]3[S:20][CH:21]=[CH:22][C:23]=3[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2sccc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncccc1CN1CCC(CC(=O)c2sccc2-c2nccs2)CC1
Yield: 99 %

Procedure:
300 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine obtained in Example 73, 438 mg of 2-(tributylstannyl)thiazole and 42 mg of tetrakis(triphenylphosphine)palladium were suspended in 4 ml of toluene, and the mixture was heated under reflux for 2 hours under nitrogen flow. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to give 300 mg of the title compound as a colorless oil.