Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=5)[CH:20]=4)[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:25]=[CH:26][CH:27]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:43][CH:44]=1
Reactant: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Yield: 8.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfon amide (250 mg, 0.39 mmol) was hydrolyzed with lithium hydroxide (66 mg, 1.6 mmol) in THF/water/methanol (4/3/1 ml) mixture to afford 15 mg (9.57% yield) of the pure product after purification by prep TLC using 2% methanol in DCM as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 11.79 (s, 1H), 9.83 (s, 1H), 8.469 (s, 1H), 8.33-8.31 (d, 2H), 7.91 (s, 1H), 7.75 (s, 1H), 7.52-7.43 (m, 3H), 7.27-7.22 (t, 3H), 6.91-6.89 (d, 2H), 5.28 (s, 2H), 3.72 (s, 3H), 3.05 (s, 3H). MS: m/z=474.2 (M+1), HPLC: 94.18% in Method-C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K2CO3 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2, 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.
Reaction SMILES: [Na].[C:2]1([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.O>CO>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]2[C:16]=1[CH:17]=[CH:18][CH2:19]2
Reactant: C1=CCC=C1
Reactant: CC(=O)CCC(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ccccc2)c2c1C=CC2
Temperature: 0 °C

Procedure:
5 g (0.21 mol}of sodium were dissolved in 100 ml of methanol in a Schlenk tube and the solution was cooled to 0° C. A mixture of 15.8 g (0.84 mol) of 1-phenyl-1,4-pentanedione and 7.3 ml (5.8 g, 0.08 mol) of cyclopentadiene was added dropwise in the course of 15 minutes. The red solution was stirred at room temperature overnight, hydrolyzed with 200 ml of water and extracted five times with 75 ml of petroleum ether each time. The combined organic extracts were filtered and concentrated to dryness and the residue was subjected to fractional distillation.
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([OH:27])=[O:26])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:55]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63](=[N:67][O:68][CH3:69])[C:64](O)=[O:65])[N:62]=1)=[O:56]>C(OCC)(=O)C.CN(C)C=O>[CH:55]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63](=[N:67][O:68][CH3:69])[C:64]([NH:1][CH:2]2[C:28](=[O:29])[N:4]3[C:5]([C:25]([OH:27])=[O:26])=[C:6]([CH2:9][S:10][C:11]4[S:12][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:65])[N:62]=1)=[O:56]
Reactant: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Yield: 62.6 %

Procedure:
A solution of 7-amino-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (4.6 g), trimethylsilylacetamide (7.86 g) and bis(trimethylsilyl)acetamide (4.0 g) in ethyl acetate (50 ml) and a solution of dimethylformamide (0.804 g), phosphoryl chloride (1.69 g) and 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 12.3 g) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 4.2 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[CH:19]=2)=[C:13]([Cl:28])[CH:12]=1>CN(C=O)C.S(=O)(O)[O-].[Na+].O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[C:19]=2[Cl:1])=[C:13]([Cl:28])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-Chlorosuccinimide was (13.0 g, 99.0 mmol) added to a suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (24) (32.54 g, 89.9 mmol) in DMF (500 mL). The suspension was allowed to stir at room temperature overnight. The reaction mixture was diluted with saturated sodium bisulfite (200 mL) and water (1 L) resulting in formation of a thick white precipitate which was isolated by filtration and washed with water. The solids were dissolved into THF. Two volumes of diethyl ether were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to provide an orange solid. The solid was triturated with diethyl ether to provide the desired product as an off-white solid (25) (13.34 g, 37%). MS (APCI−) m/z 393, 395, 397 (M−; Cl, Br pattern) detected.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:8]1([C:5]2[O:4][C:3]([CH2:2][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ncc(-c2ccccc2)o1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cnc(CN3CCN(c4ccccc4)CC3)o2)cc1

Procedure:
A solution of 2-choromethyl-5-phenyloxazole (3.87 g; 0.02 mole) and N-phenylpiperazine (3.25 g; 0.02 mole) in absolute ethanol (60 ml) was boiled and stirred with finely powdered anhydrous sodium carbonate (5 g) for 6 hours.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[N:8]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2
Reactant: Cc1c(C(O)CN2CC3CCC(C2)N3)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of isomer (37A) of 5-[2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (53 mg, 0.175 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (57 mg, 0.210 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) and then separated by SFC chiral chromatography to obtain two separated isomers A and B of 5,5′-[3,8-diazabicyclo[3.2.1]octane-3,8-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[C:7](=O)([OH:9])[O-:8].[Na+]>O>[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5].[C:7](=[O:9])=[O:8]
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C=O

Procedure:
The method of claim 1, where a portion of the stripped porduct from step five containing sodium carbonate and sodium bicarbonate is heated under pressure to above 125° C. to decompose the sodium bicarbonate contained and form sodium carbonate and carbon dioxide, and carbon dioxide and water vapor are released for use in heating in step seven.
Reaction SMILES: [Na+].C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:50])[C@@H:20]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][C@@H:45]([NH2:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:36][CH:35]=3)[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[C:26](=[O:32])[C:25]3=[O:33])=[O:23])[C:16](=[O:51])[N:11]2[C:12]=1[C:13]([O-:15])=[O:14])(=O)C.CN(C)CC[N:56]1[C:60]([SH:61])=[N:59][N:58]=[N:57]1>>[CH3:12][N:11]([CH3:16])[CH2:10][CH2:17][CH:6]([S:61][C:60]1[NH:59][N:58]=[N:57][N:56]=1)[C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:50])[C@@H:20]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][C@@H:45]([NH2:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:36][CH:35]=3)[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[C:26](=[O:32])[C:25]3=[O:33])=[O:23])[C:16](=[O:51])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CN(C)CCn1nnnc1S
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(COC(C)=O)CS[C@H]23)c2ccc(NC(=O)OC[C@@H](N)C(=O)O)cc2)C(=O)C1=O
Agent: [Na+]
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C(CCN(C)C)Sc4nnn[nH]4)CS[C@H]23)c2ccc(NC(=O)OC[C@@H](N)C(=O)O)cc2)C(=O)C1=O
Reaction time: 4 h

Procedure:
2.3 g of 3-acetoxymethyl-7β-{(2R)-2-[4-((2R)-2-amino-2-carboxyethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid sodium salt and 1.16 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole are dissolved in 12 ml of twice-distilled and degassed water. The solution is then adjusted to a pH of 6.2 with 1N aqueous NaOH and then stirred at 65° for 4 hours under a nitrogen atmosphere. It is then cooled, adjusted to a pH of 5 with 1N HCl and introduced into 600 ml of ethanol. The resulting precipitate is filtered with suction, washed with alcohol and ether and dried. The crude product is then separated over a column of 100 g of silylated silica gel (Opty-Up C 12; ANTEC AG, CH-4431 Bennwil) and 40 ml fractions are taken. Fractions 1-13 are eluted with H2O/acetonitrile (97:3), fractions 14-20 with H2O/acetonitrile (93:7), fractions 21-28 with H2O/acetonitrile (9:1) and the later fractions with H2O/acetonitrile (4:1). By concentrating by evaporation and reprecipitating from H2O/ethanol fractions 33-35, 3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7β-{(2R)-2-[4-((2R)-2-amino-2-carboxyethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid is obtained. Decomposition from 165°. [α]D20 =+34°±1° (0.67% in H2O). IR: 3400 (shoulder), 3280 (wide), 1770, 1720, 1680, 1612, 1515 cm-1 (Nujol).
Reaction SMILES: [CH:1]1([N:7]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:14][C:13]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[N:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31]1(N[C@H]2CC[C@H](C)CC2)CCCCC1.C(OC(=O)CN(S(C1SC(N)=NN=1)(=O)=O)C)C>>[CH:1]1([N:7]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:14][C:13]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:31])(=[O:17])=[O:16])=[N:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2nnc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: CCOC(=O)CN(C)S(=O)(=O)c1nnc(N)s1
Product: CN(CC(=O)O)S(=O)(=O)c1nnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared in a similar manner to {5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazole-2-sulfonylamino}-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and [(5-amino-1,3,4-thiadiazole-2-sulfonyl)-methyl-amino]-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([NH:9][C@H:10]3[CH2:13][C@H:12]([N:14]4[C:18]5[N:19]=[C:20](SC)[N:21]=[CH:22][C:17]=5[C:16]([CH3:26])([CH3:25])[C:15]4=[O:27])[CH2:11]3)[S:8][C:4]=2[CH:3]=1.C([SiH](CC)CC)C>O1CCCC1.[Pd]>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([NH:9][C@H:10]3[CH2:11][C@H:12]([N:14]4[C:18]5[N:19]=[CH:20][N:21]=[CH:22][C:17]=5[C:16]([CH3:25])([CH3:26])[C:15]4=[O:27])[CH2:13]3)[S:8][C:4]=2[CH:3]=1
Reactant: CSc1ncc2c(n1)N([C@H]1C[C@H](Nc3nc4ccc(F)cc4s3)C1)C(=O)C2(C)C
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccc(F)cc4s3)C2)c2ncncc21
Temperature: 25 °C

Procedure:
7-(Trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-5,5-dimethyl-2-(methylthio)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (EXAMPLE 156) (0.200 g, 0.466 mmol) was dissolved in dry tetrahydrofuran (10 mL) under nitrogen. Palladium (10 wt. % on activated carbon, 0.080 g, 0.075 mmol) was added followed by triethylsilane (0.200 ml, 1.252 mmol). The suspension was stirred at room temperature. After 40 minutes additional triethylsilane (0.5 mL) was added and the reaction stirred for another 4 hours. Additional palladium/carbon (0.122 g) and triethylsilane (0.25 mL) were added and the reaction stirred for another 55 minutes. The mixture was filtered through a pad of CELITE® and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-5% methanol in dichloromethane gradient) gave 7-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.091 g, 0.237 mmol, 51.0% yield) as a white solid. m/z: 384.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 1.42 (s, 6H) 2.42-2.53 (m, 2 H) 3.38-3.53 (m, 2 H) 4.55-4.65 (m, 1 H) 5.15-5.27 (m, 1 H) 7.03 (td, J=9.0 Hz, 2.6 Hz, 1H) 7.32 (dd, J=8.2 Hz, 2.6 Hz, 1H) 7.49 (dd, J=8.9 Hz, 4.7 Hz, 1H) 8.33 (s, 1H) 8.84 (s, 1H).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C(O)(=O)/C=C\C(O)=O.[NH2:17][C:18]1[N:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23]2[C:19]=1[NH:20][C:21](=[O:45])[N:22]2[CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C(O[BH3-])(=O)C.[Na+].[CH:59]([C:61]1[CH:62]=[C:63]([CH2:67][C:68]([O:70][CH3:71])=[O:69])[CH:64]=[CH:65][CH:66]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1.O>[NH2:17][C:18]1[N:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23]2[C:19]=1[NH:20][C:21](=[O:45])[N:22]2[CH2:32][CH2:33][CH2:34][N:35]([CH2:59][C:61]1[CH:62]=[C:63]([CH2:67][C:68]([O:70][CH3:71])=[O:69])[CH:64]=[CH:65][CH:66]=1)[CH2:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [BH3-]OC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCOCC3)Cc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a suspension of 6-amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)amino]propyl}-8-oxo-7,9-dihydro-8H-purine dimaleate (15.00 g, 23.45 mmol) in NMP (54.08 g) was added triethyamine (7.12 g, 70.35 mmol) at 25° C. Then sodium acetoxyborohydride (8.45 g, 39.87 mmol) was added thereto, followed by stirring at 25° C. for 15 minutes. After adding methyl (3-formylphenyl)acetate (6.27 g, 35.18 mol) and stirring at 25° C. for 8 hours, the mixture was cooled to 5° C. and then diluted with cold water (240.00). After adjusting pH to 7 with 10% sodium carbonate solution, a seed crystal was added thereto. After stirring for additional 15 minutes, the mixture was adjusted to pH 8 with 10% sodium carbonate solution and thereto was added water (15 g). After keeping at 5° C. for 1 hour, the resulting white solid was filtered, washed and dried to give the subject compound (12.10 g, 90.6%). The seed crystal used in the above was obtained by the method of the above example 5 without adding a seed crystal as the method of the above Example 5. Purity: 94.81% (HPLC)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:38][N:39](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:38][NH:39][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)[N:9]=2)[CH2:26][CH2:27]1)=[O:32]
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General procedure to EXAMPLES 37 and 38: A DMF solution (2 mL) of acid trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (100 mg, 0.23 mmol) and methylamine hydrochloride (153 mg, 2.26 mmol) in a sealed tube was charged with DIEA (394 μL, 2.26 mmol), 0.6 M HOAt in DMF (377 μL, 0.23 mmol), and then EDC (65 mg, 0.34 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 2% ˜7 N NH3 in MeOH/CH2Cl2 to 5% ˜7 N NH3 in MeOH/CH2Cl2] to afford trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide as an off-white solid (60 mg, 57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCOCC>[CH2:24]([O:23][C:21]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 67 %

Procedure:
To a solution of 3.0 g (0.013 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.4 g (0.013 mole) triethylamine, and 75 ml ether was added 1.4 g (0.013 mole) ethyl chloroformate. The reaction mixture was refluxed for 2 hours, filtered, and rotary evaporated under aspiration to give a dark oil. This was triturated with petroleum ether and the solution decanted from tars. The solvent was stripped in vacuo and the product distilled to give 2.7 g (67% yield; bp0.5 mm 125° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [NH2:1][C:2](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][C:30]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:8][N:7]([CH2:6][C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]2[N:1]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]4[CH3:22])=[C:30]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:31]=3)[O:21][N:20]=2)[CH:4]=1)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Product: CC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 51 (440.05 mg; 1.50 mmol), and Intermediate 25 (562.30 mg; 1.80 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography over Alumina column (c-hex/EtOAc: 9.5/0.5), affording the title compound as an off-white powder. HPLC (Method A) Rt 4.76 min (Purity: 96.7%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[C:3]#[CH:4].CN(C)C=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[F:43])[O:24][C:25]1[N:30]=[C:29]2[S:31][C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])=[N:33][C:28]2=[CH:27][CH:26]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[S:31][C:29]3[C:28]([N:33]=2)=[CH:27][CH:26]=[C:25]([O:24][C:23]2[CH:40]=[CH:41][C:42]([F:43])=[C:21]([NH:20][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[CH:7]=4)[CH:22]=2)[N:30]=3)=[O:36])[CH2:38][CH2:39]1
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (0.10 g, 0.5 mmol) in oxalyl chloride (1 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixed solution of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.12 g, 0.33 mmol) produced in Example C63(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (62 mg, 37%) as colorless crystals.