Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)=O)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCO>O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Clc1ccc(Cc2ccc[nH]2)cc1

Procedure:
Heat 20 g of 2-(4-chlorobenzoyl)pyrrole, 15 g of hydrazine hydrate, 28 g of potassium hydroxide and 100 ml of diethylene glycol to 150° for 2 hours. Allow the mixture to cool. Dilute it with water to twice its volume. Add hydrochloric acid to it until its pH is about 3 before extracting it with diethyl ether. Free the organic phase from solvent to obtain 2-(4-chlorobenzyl)pyrrole as oil remaining behind. Dissolve the oil in 25 ml of ethanol, and add this solution dropwise to a boiling mixture of 150 ml of 20% strength hydrochloric acid and zinc amalgum (prepared from 100 g of zinc, 10 g of mercury chloride and 150 ml of 0.5 N hydrochloric acid). Then add a further 200 ml of 20% strength hydrochloric acid and 50 g of amalgam and boil the resulting reaction mixture for a further 4 hours. Allow the mixture to cool, filter it, extract the filtrate with ethyl acetate (5×200 ml), concentrate the organic solution, add 6 N sodium hydroxide solution to the concentrate until zinc salts therein dissolve, and then extract with diethyl ether. Concentrate the ether solution. Dissolve the oil remaining behind in 200 ml of ethanol and hydrogenate on Pt/C contact. Filter the catalyst from the hydrogenated product. Concentrate the filtrate and then distil the concentrate under a vacuum to obtain the title compound [b.p. 76° to 79° at 0.005 mm of Hg]. The hydrochloric melts at 190° to 192°.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[CH:21][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][N:24]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2ncc(-c3ccccc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and phenylboronic acid as starting materials and by an operation similar to that of Example 162-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained solid was triturated and washed with hexane-ethyl acetate to give the title compound as a white solid.
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:25]I.O[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][S:37]([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[I:25][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: II
Reactant: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CI)c(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (4.5 g, 66.6 mmol) and PPh3 (17.4 g, 66.6 mmol) in DCM (180 mL) is slowly added over a period of 10 min of I2 (16.9 g, 66.6 mmol) and it is stirred at RT for 30 min. Then a solution of methanesulfonic acid 2-hydroxymethyl-5-methylphenyl ester (12.0 g, 55.5 mmol) in DCM (40 mL) is added drop wise and it is stirred at RT for 1 h. The reaction mixture is concentrated to about 70 mL. It is then filtered and washed with DCM. The filtrate is concentrated and purified to give the title compound as a solid.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](Br)[CH:12]=[CH2:13].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:13]([C:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:12]=[CH2:11]
Reactant: COC(=O)C1CCCCC1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)CCCCC1
Temperature: 50 °C
Reaction time: 64 h
Yield: 18.7 %

Procedure:
To a solution of methyl cyclohexylcarboxylate (1.42 g) and allyl bromide (3.02 g) in N,N-dimethylformamide (20 mL) was added potassium tert-butoxide (1.68 g, 15.0 mmol) under ice cooling. The solution was stirred at room temperature for 16 hours, at 50° C. for 8 hours and further at room temperature for 64 hours. Water and 3N hydrochloric acid were then added to the solution, and it was extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=97:3) to give the title compound (340 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:24]([Cu])#[N:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2cc(Cc3ccccc3)ccc2c1O
Product: COC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O

Procedure:
The title compound was synthesized from 7-benzyl-1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=317.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:31]([CH3:33])[CH3:32])[C:14]=2[N:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:30][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:31]([CH3:33])[CH3:32])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NC(=O)Nc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
1-Fluoro-2-isocyanato-benzene (48.5 mg, 035 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methyl-pyridin-4-yl)-methanone (100 mg, 0.32 mmol) in pyridine (2 mL). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo. The resulting residue was triturated with MeOH, filtered, and dried to afford the title compound as an off-white solid (104 mg, 72%). MS: 448.3 (MH+); HPLC Rf: 6.36 min. (HPLC method 4).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:19].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1(C)C=CC=CC=1>[O:31]=[S:29]1(=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:11]3[C:6]([C:5]=2[OH:19])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:32]1
Reactant: CCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of Example 26F (0.092 g, 0.287 mmol) and 2-amino-benzenesulfonamide (0.052 g, 0.301 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.113 g, 99%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:60][O:61][C:62](=[O:65])[CH2:63]Br>CCOCC.C(Cl)Cl>[C:62]([CH2:63][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1)([O:61][CH3:60])=[O:65]
Reactant: COC(=O)CBr
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.126 g (0.258 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 6 mL of ether was added 0.082 g (0.31 mmol) of 18-crown-6 and 0.31 mL (0.31 mmol) of potassium t-butoxide (1M in t-BuOH). After stirring the reaction mixture at rt for 15 min, the reaction mixture was cooled to 0° C. and to it was added 0.034 mL (0.36 mmol) of methyl-2-bromoacetate. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with sat. NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated and purified by chromatography (silica, hexanes: acetone, 3:1) to give the title compound.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CO>[C:11]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])=[CH:23][CH:24]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CO
Product: CSC(Nc1ccc(NC(=O)OC(C)(C)C)cc1)=C(C#N)C#N
Temperature: 25 °C

Procedure:
A mixture of 13.89 g (81.58 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 17 g (81.63 mmol) of N-BOC-1,4-phenylenediamine (Fluka) and 200 ml of methanol is heated under reflux for 5 hours. Cooling to room temperature, filtering and washing the filter residue with methanol yield the title compound; m.p. 190° C. Concentration of the filtrate by evaporation and recrystallization of the residue from 50 ml of methanol yield a further batch of the title compound; m.p. 190-191° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2c(C)cccc2[nH]1
Product: Cc1cccc2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-methyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 314.1 ([M−H]−).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>>[NH:19]1[C:18]([NH:17][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=2)=[O:12])=[N:22][N:21]=[N:20]1
Reactant: CCCc1cccc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CCCc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 9.9 %

Procedure:
1.9 g of 6-n-propyl-2-pyridinecarboxylic acid, 12 ml of thionyl chloride and 0.96 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.26 g of N-(5-tetrazolyl)-6-n-propyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:19][CH:18]3[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]3)[CH2:14][C:13]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][C:9]1[CH:22]=[C:13]2[C:12](=[CH:11][CH:10]=1)[CH2:19][CH:18]1[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]1)[CH2:14]2)[CH3:7]
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(c1)CC1CCC(C2)C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
Ethyl bromoacetate (8.01 g) was added to a stirred solution of [6S/R,9R/S]2-Hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (9.7 g; J. Org. Chem 1982, 47, 4329) and potassium carbonate (6.6 g) in dry DMF (150 mL). The reaction was warmed to 90° C. for 18 hours, cooled to room temperature, diluted with water (200 mL), and extracted into ether (4×100 mL). The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash chromatography over silica (200–400 mesh, 0–30% EtOAc/isoHexane) afforded (13-oxo-tricyclo[8.2.1.03,8]trideca-3,5,7-trien-5-yloxy)-acetic acid ethyl ester (11.07 g) 1H NMR (CDCl3 400 MHz) δ 1.28 (3H, m), 1.84 (2H, m), 2.58 (2H, m), 2.86 (4H, m), 4.15 (2H, m), 4.22 (2H, m), 4.59 (2H, s), 6.71 (1H, dd, J=8.0, 4.0 Hz), 6.80 (1H, d, J=4.0 Hz), 7.10 (1H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>>[C:1](=[NH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N
Product: N=C(c1ccccc1)c1ccccc1

Procedure:
In particular, m=n=0, i.e. benzophenone is used for reaction with ammonia to give benzophenone imine.
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12>ClCCl.N1C=CC=CC=1>[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:9](=[O:10])[CH2:8][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:12])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12
Reactant: C[C@H](CC(=O)Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)C[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
(3R)-3-Phenylbutanoyl chloride (2.22 g, 12.18 mmol) in dichloromethane (10 mL) was added to a solution of 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (2.86 g, 8.12 mmol) in pyridine (50 mL) at −10° C. After 15 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. Sodium hydroxide (1.0N, 15 mL) was added and the organic solvent was evaporated. The aqueous residue was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (95:5) as mobile phase to give N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-(3R)-3-phenylbutanamide (3.11 g, 77%). 1H NMR (CDCl3) δ 1.40 (d, J=6.97 Hz, 3H), 2.04 (m, 1H), 2.59-2.78 (m, 9H), 3.40 (m, 1H), 3.98 (s, 3H), 5.28 (m, 1H), 5.70 (bs, 2H), 7.15-7.35 (m, 7H), 7.66 (s, 1H), 8.38 (s, 1H), 8.51 (d, J=8.18, 1H). HPLC (Waters Alliance-Column: Waters SymmetryShield, RP18, 3.5 um, 2.1×50 mm. Eluents: 5% B/A to 95% B/A in 9.0 min.(B: acetonitrile, A: 100 mM ammonia acetate buffer, pH 4.5), 0.5 mL/min.): Rt=6.273 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1)(C)(C)C.Cl>>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Agent: Cl
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method K, {3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (I-39) was converted to the HCl salt of I-38 (30%): HRMS Calcd. for C23H21N5O3 416.1720, Found 416.1722.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4].CO>O1CCCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4]
Reactant: CC#CCCC(=O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Reaction time: 1 h

Procedure:
At -40°, 420 mg. of sodium borohydride is added in incremental portions to a solution of 800 mg. of (1S,5R,6R,7R,3R)-7-acetoxy-6-[(E)-3-oxo-1-octen-6-ynyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 24 ml. of methanol and 10 ml. of tetrahydrofuran. The mixture is agitated for 1 hour at -40°. Then the mixture is gently combined with 1 ml. of glacial acetic acid, concentrated under vacuum, the residue combined with methylene chloride, the organic extract shaken with 4% sodium bicarbonate solution, washed neutral with water, dried with magnesium sulfate, and evaporated under vacuum. After chromatography of the residue on silica gel with ether/pentane (6+4), 250 mg. of the corresponding compound in the β-configuration is obtained, along with 266 mg. of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8])=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1c(C=O)c(C)n(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(CO)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 10.9 g of ethyl 4-formyl-1,2,5-trimethylpyrrole-3-carboxylate in 40 ml of methanol is added dropwise under nitrogen 5.6 g of sodium borohydride in methanol while maintaining the reaction temperature below 50° C. after total addition the reaction mixture is stirred at ambient temperature for 4 hours, then 90 ml of water introduced and the reaction mixture saturated with potassium carbonate and extracted with ether. The combined ether extracts are dried and concentrated in vacuo leaving a yellow solid which is recrystallized from cyclohexane to give ethyl 4-(hydroxymethyl)-1,2,5-trimethylpyrrole-3-carboxylate, mp 184°-186° C.
Reaction SMILES: Cl[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55](Cl)=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36](Cl)=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3].[OH:60][CH2:61][CH2:62][NH:63][CH2:64][CH2:65][OH:66]>C1C=CC=CC=1.O>[OH:60][CH2:61][CH2:62][N:63]([CH2:64][CH2:65][OH:66])[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3]
Reactant: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)Cl)OC(C)(C)S3)S1
Reactant: OCCNCCO
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)N(CCO)CCO)OC(C)(C)S3)S1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Tris-(8-chlorocarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:5,4-d']-bis(1,3)oxathiol-4-yl)methanol (0.80 g, 0.80 mmol) was dissolved in benzene (200 mL). A solution of of bis(2-hydroxyethyl)amine (8.0 g, 48 mmol) in water (200 mL) was added and after vigorous stirring overnight, the mixture was transferred to a separatory funnel. The aqueous layer was removed and the remaining solid plus the benzene layer was evaporated, dissolved in methanol and passed through a short column (neutral alumina). After elution of unwanted materials with acetonitrile, the amide was eluted with methanol. After evaporation, the product was stirred with water (50 mL) at 40° C. for 2 h and then isolated by filtration. After drying, 0.60 g (60%) of the pure amide was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:5]2[S:1][C:2]([N:6]3[CH:10]=[CH:9][CH:8]=[N:7]3)=[CH:3][CH:4]=2)[CH:19]=1
Reactant: c1csc(-n2cccn2)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1ccc(-n2cccn2)s1

Procedure:
1-(2-thienyl)pyrazole (see: Chemica Scripta (1979) 13, 157-161) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 7 to give the title compound as colorless solid. APCI-Mass m/z 353/355 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:6]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Reactant: C1COCCN1
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)N5CCOCC5)c(F)c4)c3c2)o1
Yield: 78 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using morpholine instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 78%) was obtained as colorless crystals.