Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17](Cl)[NH:16][C:15]2=[O:23])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[SH2:25].[Na]>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([SH:25])[NH:16][C:15]2=[O:23])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: S
Reactant: Cc1c(Cl)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1c(S)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
The product of Example 1, Step (A) (0.54 g) was dissolved in dimethylformamide (5 mL) wand treated with sodium hydrogen sulfide (0.29 g) and heated at 60° C. for 18 hours. The solvent was removed in a vacuum and the residue stirred with 1 M hydrochloric acid (15 mL) for 1 hour. The resulting solid was filtered, rinsed with water and dried in a vacuum at room temperature to give 4-(4-mercapto-5-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl)-benzoic acid tert-butyl ester (0.475 g, 91% yield). 1H-NMR (DMSO-d6) δ 10.99 (s), 7.76(d, 2H), 7.27 (d, 2H), 5.52 (s, 2H), 1.91, (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[CH2:24]([O:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:6]=1[F:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9) (930 mg, 3.81 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in DMF (8 mL) was added benzyl chloride (0.53 mL, 4.57 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoate (752).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH:9]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12]C(C)(C)C)=[O:11])=[O:8])[CH:3]=1>FC(F)(F)C(O)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH:9]([C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])[C:10]([OH:12])=[O:11])[CH3:25]
Reactant: CCOC(=O)CCCCC(C(=O)OC(C)(C)C)C(=O)c1cc(C)on1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCC(C(=O)O)C(=O)c1cc(C)on1
Yield: 100 %

Procedure:
A solution of 1-tert-butyl 7-ethyl 2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate (126 mg) in trifluoroacetic acid (1 mL) was stirred for 1.5 hour at room temperature. The volatile was evaporated off, and azeotroped with toluene to give 7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid as a pale orange oil (106 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCCCCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=[C:21]([Br:24])[Br:20])=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cc(C=C(Br)Br)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Triphenylphosphane (17.2 g, 65.5 mmole) was added in portions at 0° C., while stirring and within 60 min to a solution of tetrabromocarbon (10.9 g, 32.7 mmole) in DCM (120 ml) and post-stirred for 1 h at 0° C. 3-formyl-indole-1-carboxylic acid-tert-butylester (4 g, 16.4 mmole) dissolved in DCM (30 ml) was subsequently added dropwise within 30 min and the mixture stirred for 4 h at 0° C. After heating the solution to RT, hexane (300 ml) was added and the mixture stirred for 30 min at RT. The mixture was suction filtered and post-washed with hexane. The filtrate was evaporated, a yellow solid being obtained. Chromatographic purification on silica gel was carried out using cyclohexane/EE (95:5). 6.26 g 3-(2,2-dibromovinyl)-indole-1-carboxylic acid-tert-butylester were obtained (white solid, mp. 101 to 104° C.). A solution of 3-(2-2,-dibromovinyl)-indole-1-carboxylic acid-tert-butylester (2.97 g, 7.4 mmole) in THF (20 ml) was introduced at −78° C. under argon, and subsequently a 1.6 M solution of n-butyllithium in hexane (5.7 ml, 9.1 mmole) was added within 30 min, the mixture stirred for 1 h at −78° C., brought to room temperature and then added to a solution, cooled to −78° C., of 4-dimethylamino-4-phenylcycohexane carbaldehyde (580 mg, 2.5 mmole) in THF (10 ml). The mixture was stirred for 8 h at −78° C., brought to room temperature and water (20 ml) was added. For working up, the aqueous phase was extracted with toluene (3×15 ml). The combined organic phase was washed with saturated NH4Cl, 0.2M NaOH and water (about 20 ml in each case), dried over sodium sulfate, filtered and evaporated. First chromatographic purification of the substance mixture obtained was carried out using acetonitrile/methanol/1M NH4Cl (9:1:1) on silica gel. Three compounds were obtained following a second column chromatographic separation with methanol on silica gel:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1.[OH:23]N1C(=O)C2=CC=CC=C2C1=O>>[CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Product: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Yield: 53 %

Procedure:
3β-methoxyandrost-5-ene-17β-ol (27) was subjected to air oxidation in the presence of N-hydroxyphthalimide and the producT 3β-methoxy-17β-hydroxyandrost-5-ene-7-one (28) was obtained in 53% yield. An analytical sample was obtained by recrystallization from acetone-hexane, m.p. 202-4° C.
Reaction SMILES: [C:1]([N:4]1[CH:8](O)[CH2:7][CH:6]([CH2:10][CH3:11])[C:5]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([CH2:10][CH3:11])[C:5]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(CC)CC(O)N1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(=O)OCC)C(CC)CCN1C(C)=O
Temperature: 25 °C
Yield: 137.6 %

Procedure:
To a solution of diethyl 1-acetyl-5-hydroxy-3-ethylpyrrolidine-2,2-dicarboxylate (287 g, 0.95 mol) and triethylsilane (228 mL, 1.43 mol) in CH2Cl2 (3 L) under argon was added trifluoroacetic acid (735 mL, 9.53 mol) dropwise with stirring while maintaining the internal temperature at 25° C. by means of an ice bath. After stirring for 3 h at 23° C., the solution was concentrated in vacuo, the residue diluted with CH2Cl2 (1.5 L), then treated with H2O (1 L) and solid Na2CO3 with vigorous stirring until the solution was basic. The organic layer was separated, dried (Na2SO4), filtered, then concentrated to give the title compound as a yellow oil (373 g) which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chilled (0° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-formyl-pyridin-4-yl)-propyl]-amide (95 mg, 0.24 mmol) in THF (2 mL) and methanol (2 mL) was added sodium borohydride (17.8 mg, 0.47 mmol). The mixture was then warmed to room temperature. After 1.5 hours, the mixture was quenched with water (5 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]#N.Cl.C[OH:14]>[C].[Pd]>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH:10]=[O:14]
Reactant: N#Cc1cnn(CCO)c1N
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: Nc1c(C=O)cnn1CCO
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile (15 g) in methanol (300 ml) was added hydrochloric acid (1.8 ml) under ice-cooling. The resulting solution was stirred for 15 minutes. The mixture was treated with 10% palladium carbon (7.5 g) under a hydrogen atmosphere at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo to give 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (13.3 g).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:28][CH:29]([CH2:41][CH3:42])[C@@H:30]([C:32]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=1)[OH:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:28][C@H:29]([CH:30]([OH:31])[C:32]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=2)[CH2:41][CH3:42])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A solution of (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (223 mg, 0.788 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid (267 mg, 0.788 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (299 mg, 0.787 mmol) and diisopropylethylarmine (0.274 ml, 1.576 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide as a yellow solid (324 mg).
Reaction SMILES: [CH2:1]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37]CC4C=CC=CC=4)=[C:33]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:32]=3)[OH:30])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:32]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 62.1 %

Procedure:
4-(4-{2-[(2R)-2-(4-Benzyloxy-3-methanesulfonylamino-phenyl)-2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylicacid octylamide (0.152 g, 0.219 mmol) was dissolved in ethanol (40 mL) and 10% palladium on carbon (0.05 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 2 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to furnish the title compound (0.082 g, 0.136 mmol)
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[C:1]([N:15]1[CH2:16][CH2:17][S:13][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1CSCN1
Product: CCCCCCC/C=C/C(=O)N1CCSC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and thiazolidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([O:18]CC)=[O:17])[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=[O:17])[CH3:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(Br)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O

Procedure:
Ten g of the compound of Example 19 was refluxed for 10 minutes with 3.3 g of potassium hydroxide in 150 ml of ethanol, and the product was collected as described in Example 22 and recrystallized from ethanol to obtain 8.0 g of the desired product, m.p. 195°-197°.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>O1CCCC1.O.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>[CH3:9][O:8][C:7]1[C:3]([CH2:2][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([C:29]([F:46])([F:45])[F:28])[CH:35]=2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccnc(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Step D, 0.525 g, 66 weight %, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.42 g, 1.5 mmol). The mixture was heated to reflux and stirred for 17 h. The reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (25 mL, 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford the title compound (0.12 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:19])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A stirred solution of 253C (55 mg, 0.127 mmol) in DMF (1.0 mL) was treated with N1,N1-dimethylethane-1,2-diamine (0.021 mL, 0.190 mmol), BOP (72.9 mg, 0.165 mmol) and TEA (0.035 mL, 0.254 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, triturated with water, and the resulting white solid was collected by filtration to yield 253D (60.0 mg, 93.7% yield). HPLC: Rt=3.47 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=504.1 [M+H]+.
Reaction SMILES: B([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(O)O.Br[C:13]1[N:17]2[N:18]=[C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1>>[O:31]=[C:27]1[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([C:4]3[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=3)=[CH:14][N:15]=2)[N:18]=1
Reactant: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1
Reactant: O=C(O)c1ccc(B(O)O)s1
Product: O=C(O)c1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)s1
Yield: 64 %

Procedure:
The Suzuki coupling of 5-boronothiophene-2-carboxylic acid and 1-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)pyrrolidin-2-one using the procedure described in example 5.6.19 yielded 64% of the titled compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCS(=O)(=O)CC1
Yield: 23.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 65A (200 mg, 0.38 mmol), thiomorpholine 1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide (2 mL) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea (56.27 mg, 24%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.30 (bs, 2H), 3.99 (s, 3H), 3.12-3.04 (m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 627 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([O:31][C:32]2[C:37]([NH2:38])=[CH:36][N:35]=[CH:34][N:33]=2)[CH2:26]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:38][C:37]2[C:32]([O:31][C@@H:27]3[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[CH2:26]3)=[N:33][CH:34]=[N:35][CH:36]=2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Reactant: CN1CCC[C@@H](Oc2ncncc2N)C1
Solvent: CN1CCCC1=O
Product: CN1CCC[C@@H](Oc2ncncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C

Procedure:
A solution of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (125 mg, 0.3990 mmol) and 4-[[(3R)-1-methyl-3-piperidyl]oxy]pyrimidin-5-amine 7a (83.10 mg, 0.3990 mmol) in NMP (2 mL) was heated at 100° C. overnight. The reaction mixture was cooled to RT, passed through a SCX cartridge, eluting with 2M ammonia in methanol. The product fractions were combined, concentrated in vacuo and purified by HPLC. The title product I-A-1 was isolated (60 mg., 38.9%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1.[CH:18](O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[CH:18][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1NCc1cccc(F)c1
Reactant: O=CO
Solvent: CCOC(C)=O
Product: Fc1cccc(Cn2cnc3ccc(Br)cc32)c1

Procedure:
A mixture of Example 2B (299 mg, 1.013 mmol) in formic acid (500 μL, 13.25 mmol) was stirred at 90° C. for 1 hour. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with 80% ethyl acetate/hexane afforded the title compound. MS (ESI) m/e 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22]([OH:24])[CH3:23].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])[C:3]=1[O:20][CH2:21][CH:22]([O:24][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 5 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
To a solution of 2.07 g of the compound obtained in Example 6 in 4.2 ml of pyridine was added 1.49 g of p-toluenesulfonyl chloride and the mixture was stirred at an external temperature of 5° C. for 3 days. To the mixture was added ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 2.76 g of the titled compound.