Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:32])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[C:18]([S:22]([NH:25][C:26]([NH:28][CH3:29])=S)(=[O:24])=[O:23])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[OH:33]O>[OH-].[Na+]>[CH2:1]([C:3]1[C:4](=[O:32])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[C:18]([S:22]([NH:25][C:26]([NH:28][CH3:29])=[O:33])(=[O:23])=[O:24])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: OO
Reactant: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=S)NC)cc3C2)C1=O
Agent: [Na+]
Agent: [OH-]
Product: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=O)NC)cc3C2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1 g of 3-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-6-(methylaminothiocarbonylaminosulfonyl)-7-methoxychroman (Example 22) was suspended or dissolved in 20 ml of cold 0.5N sodium hydroxide solution. 1 ml of 37% strength hydrogen peroxide solution was added in the cold (-4° to 0° C.). The mixture was stirred at 0° C. for 1.5 hours. The crude product was precipitated by addition of 2N HCl and then purified over silica gel (eluting agent methylene chloride/glacial acetic acid 9:1). The product had a melting point of 245°-246° C.
Reaction SMILES: [BH4-].[Li+].C(O)(C)(C)C.O1CCCC1.[CH2:13]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26][Br:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.O>[CH2:13]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C@H:25]([OH:28])[CH2:26][Br:27])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: O
Product: O[C@H](CBr)c1ccc(OCc2ccccc2)cc1
Temperature: -60 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 10.8 g of (L)-dibenzoylcystine, 1 6 g of lithium borohydride, 2.4 g of tert-butanol and 180 ml of tetrahydrofuran was refluxed for 1 hour and then cooled to -60° C. Thereto was added 6.1 g of 4-benzyloxyphenacyl bromide. The mixture was stirred for 30 minutes at the same temperature and further for 3 hours at -40° to -30° C. The reaction mixture was added to a mixture of 100 ml of water and 200 ml of diethyl ether. The organic layer was separated, washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene) to obtain 2.8 g of (S)-1-(4-benzyloxyphenyl)-2-bromoethanol.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)4acetylxanthen-9one (2.4 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%, the addition being performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized with methanol to give 1.9 g of product m.p. 134-36° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 3.84 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.95-6.98 (m, 1H); 7.05-7.15 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.09 (d, 1H, J=16 Hz); 7.23-7.42 (m, 4H); 7.65-7.72 (m, 1H); 8.32-8 (d, 1H. J=8.8 Hz); 8.42(d, 1H. J=8.9 Hz).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@H:16]2[C@@H:15]([O:23]S(C(F)(F)F)(=O)=O)[CH2:14][N:13]1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O-])(=[O:44])[CH3:43].[Cs+].C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@H:15]([O:23][C:42](=[O:44])[CH3:43])[CH2:14][N:13]1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:32])=[O:33])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](OC(C)=O)[C@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
The above compound (2-1) (670 mg) was dissolved in acetonitrile (30 mL) and cesium acetate (0.5 g) and 18-Crown-6 (1.4 g) were added, and then the mixture was stirred at room temperature for 16 hours, To the reaction solution was added ethyl acetate (100 mL) and, after washing in turn with dilute hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and saturated saline, the solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3→1:1) to obtain the titled compound (161 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[NH2:28][C:29]([NH2:31])=[S:30]>>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:14])[C:9]2[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:18][C:8]3=2)[N:28]=1
Reactant: NC(N)=S
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(N)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 21 above, using compound from Example 114A 6-(2-bromoacetyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and thiourea.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH2:34][C:33]([CH2:35]Br)=[CH:32][CH2:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH2:34][C:33]([CH2:35][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:32][CH2:31]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CCC(CO)C2)c1
Yield: 33.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound (73 mg)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:14]([OH:16])[CH3:15])[C:3]=1[O:17][CH3:18].Cl.CN(C)CCCN=C=NCC.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:14]([O:16][C:31](=[O:33])[CH3:32])[CH3:15])[C:3]=1[O:17][CH3:18]
Reactant: COc1c(C(C)O)cc2c(c1Br)C(C)(C)CCC2
Reactant: CC(=O)OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C(C)OC(C)=O)cc2c(c1Br)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-bromo-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanol (Compound A-95, 12.3 g, 39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 11.2 g, 58.5 mmol) and 4-dimethylaminopyridine (DMAP, 9.5 g, 78 mmol) in dichloromethane (350 mL) at room temperature was added acetic anhydride (3.7 mL, 39 mmol). After stirring at room temperature for 16 h, the mixture was quenched with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].C=O.[C:38](O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([CH3:38])[CH2:27][CH2:28]4)=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCC1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
After dissolving N-(2-chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea (540 mg, 0.846 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml), there were added 37% aqueous formaldehyde (1 ml), acetic acid (0.10 ml, 1.69 mmol) and sodium cyanoborohydride (106 mg, 1.69 mmol) at room temperature, and the mixture was stirred for 1 hour. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (282 mg, 0.557 mmol, 65.9%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[N:6][C:5]([C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([NH:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:18])[CH:14]=2)=[CH:4][N:3]=1
Reactant: CCNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Reaction time: 18 h
Yield: 42 %

Procedure:
Methyl 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.6 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH of 4 with concentrated HCl. A white solid precipitated and was collected, washed with water and dried in vacuo to give 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoic acid (445 mg, 97% yield). The pyrazine acid (40 mg, 0.14 mmol) was dissolved in DMF (1 mL), and then 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour benzylamine (30 mg, 0.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution then brine and dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-ethyl-6-(3-{[(phenylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (a tan color solid, 22 mg, 42% yield): 1H NMR (400 MHz, DMSO-d6): 9.14 (s, 1H), 8.88 (s, 1H), 8.87-8.85 (b, 1H), 8.51 (s, 1H), 8.37-8.34 (d, 1H), 7.87-7.85 (d, 1H), 7.63-7.59 (b, 1H), 7.58-7.54 (t, 1), 7.34-7.23 (m, 4H), 4.53-4.52 (d, 2H), 3.38-3.29 (m, 2H), 1.171.14 (t, 3H); MS (EI) for C21H21N5O2: 376 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:29]>C(O)C>[Na+:29].[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:23][CH:24]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)[O-])cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
An amount of 8.4 gm (0.0229 mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid was dissolved at 60° to 65° C. in 80 ml of ethanol. To this solution 22.9 ml of 1N sodium hydroxide solution were added under stirring, and stirring was continued for 30 minutes. After cooling to 20° C., a precipitate was thereby obtained. After further cooling to 0° C., the precipitate was filtered and washed with cold ethanol and ether. The precipitate thus obtained (m.p.: 250°-251° C.) was recrystallized from ethanol/water (7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1.[CH:27]([NH2:29])=[O:28]>ClCCl.CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc(COc2nnc(Nc3ccc(Cl)cc3)c3ccccc23)ccn1
Yield: 10 %

Procedure:
The general procedure used for the preparation of Example 4 was used to prepare 5 from 1-(4-chlorophenylamino)-4-(4-pyridylmethoxy)phthalazine and formamide; (10% yield). TLC (dichloromethane/acetone/triethylamine 7.5:1.0:0.5): Rf=0.42.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)O[SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([CH2:7][C:8]#[C:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)O[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: OC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 3-phenylpropionaldehyde (136 mg, 1.0 mmol) and 1,1,1,3,3-pentamethyldisiloxane (371 mg, 2.5 mmol) were added through a syringe, and iron complex A (5 mg, 0.01 mmol) was admitted as catalyst. The solution was stirred at room temperature for 3 hours. At 0° C., THF (1 mL) and tetrabutylammonium fluoride in THF (1 M, 1 mL) were then added to the solution, which was stirred at 0° C. for 1 hour. THF was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 3-phenylpropyne-1-ol (120 mg, 0.88 mmol, 88%). The results are shown as Entry 1 in Table 6. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH2:23]([O:21][C:20](=[O:22])[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
In a 200 ml 3 neck flask equipped with a Dean and Stark trap, reflux condenser (with drying tube attached), and mechanical stirrer, 15 grams (0.0789 mole) of p-toluenesulfonic acid monohydrate is refluxed until one equivalent of water is released. At this point 10 grams (0.07634 mole) leucine and 17.0 grams (0.15 mole) benzyl alcohol are added. The mixture is refluxed for 4 hours and allowed to cool to room temperature. The solvents are removed in vacuo and a white, solid residue is produced. The white solid is washed with anhydrous ether and recrystallized from ethanol/ether to yield in three crops 28.2 grams of leucine benzyl ester p-toluene sulfonate (94% yield) having a melting point of 157°-158° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][C:64]=1[CH3:65]>ClCCl.CCOC(C)=O>[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH:67][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:62]=[CH:63][C:64]=1[CH3:65]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
6-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (2 g, 4.42 mmol) was partially dissolved in dichloromethane (100 mL), and HBTU (1.676 g, 4.42 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.884 g, 4.42 mmol), and TEA (1.232 mL, 8.84 mmol). The mixture was allowed to stir under argon over night at room temperature. The reaction was not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was added and the mixture was again stirred overnight. The reaction was still not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was again added and the mixture was stirred overnight. The reaction mixture was taken up in EtOAc (100 mL) and washed 3× with water (50 mL). Solid was recovered and washed with water and ethyl acetate. Drying the solid under vacuum gave N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1.97 g, 2.95 mmol, 66.7% yield). The ethyl acetate layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give another batch. This batch was taken up in methylene chloride and absorbed on Isolute® Sorbent (Biotage, Uppsala, Sweden; http://www.biotage.com/) and purified with a Combiflash on an 80 g silica column eluted with 0-10% DCM/MeOH. Product fractions were combined and evaporated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (704 mg, 0.987 mmol, 22.34% yield) as a white solid. LC-MS m/z 435 (M+H)+, 0.94 min (ret time).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Reactant: Cc1cncc(Br)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 3-bromo-5-methylpyridine.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)(O)[O-].[Na+].CC(C)=O.O.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:30][C:31](=[O:32])[NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccc(-c2nnco2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of 3-(1,3,4-oxadiazol-2-yl)aniline (1 g, 6.2 mmol) and sodium bicarbonate (1.1 g, 13 mmol) in a 2:1 mixture of acetone/water (10 mL) was cooled to 0° C. Benzylchloroformate (0.92 mL, 6.5 mmol) was added dropwise over 5 minutes. The reaction mixture was brought to room temperature and stirred for 30 minutes at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and filtered on a glass flit to give (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester as a white powder (1.7 g, 93%). M+1=296.4
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:2]2[CH2:3][CH2:4][C:5]3[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=4[S:7][C:6]=3[C:1]2=[O:14])=[CH:22][C:23]([F:27])=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: O=C1NCCc2c1sc1c2CCCC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 76.2 %

Procedure:
A solution of 103e (3 g, 14.5 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101j (14 g, 43.5 mmol), Xantphos (839 mg, 1.45 mmol), Pd2(dba)3 (1.33 g, 1.45 mmol) and Cs2CO3 (9.4 g, 29 mmol) in dioxane (200 mL) was heated at 100° for 15 h under nitrogen. After filtration, the filtrate was evaporated in vacuo and purified by flash column eluting with ethyl acetate/petroleum ether (1:1) to give 103f (5 g, yield 77%) as a yellow solid. LCMS: (M+H)+452. 1H NMR (500 MHz, DMSO) δ 7.71 (dd, J=2.5, 1H), 7.51 (dd, J=3, 1H), 5.04 (m, 1H), 4.10 (m, 1H), 3.68 (m, 1H), 2.86 (m, 2H), 2.77 (m, 2H), 2.55 (m, 3H), 1.98 (s, 3H), 1.78 (m, 4H)