Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=O.[CH2:10]([C:17]1[NH:25][C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.NN.[H][H]>[Pd]>[NH2:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][N:20]2[C:19]3[N:18]=[C:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:25][C:24]=3[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:21]2=[O:33])=[CH:41][CH:40]=1
Reactant: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)CCCN=C=O
Agent: NN
Solvent: O
Product: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art 3-dimethylaminopropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine, which in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)xanthine.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ncccn1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1ncccn1

Procedure:
Reaction of 2-bromopyrimidine with 1,3-diaminopropane in ethanol containing sodium ethoxide gives 2-(3-aminopropylamino)pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (20 mmol, 1 equiv) in DMF was added NaN3 (2.5 equiv, 50 mmol), the resulting mixture was heated to 65 centigrade and stirred overnight. The mixture was diluted with water, extracted with AcOEt and dried over Na2SO4. After removal of solvent, the residue was purified by chromatography on silica gel to give title product (4.94 g) as colorless oil in 90% yield. MS m/e=271.5 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=2[CH:29]=1
Reactant: CCNCC1COc2ccccc2O1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccccc2O1
Temperature: 76 °C
Yield: 51.6 %

Procedure:
N-Ethyl-2,3-dihydro-1,4-benzodioxin-2-methanamine (4.67 g, 24.2 mmole), 7-(3-bromopropoxy)coumarin (6.92 g, 24.4 mmole), and diisopropylethylamine (6.70 ml, 38.5 mmole) were combined in 300 ml of DMF and heated at 76° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue (10 g) was column chromatographed on 225 g of silica gel using 40% ethyl acetate/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the residue crystallized from isopropanol with the addition of 30 ml of 4N isopropanolic HCl to give 4.94 g of the title compound as a white solid, monohydrochloride, m.p. 147°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@:7]2([CH3:27])[N:11]3[C:12]([C:15](O)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl.[CH2:31]([O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([O:34][C:35]([C:37]1([NH:40][C:15]([C:12]2[N:11]3[C@@:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:29][CH:28]=4)([CH3:27])[C:8](=[O:26])[N:9]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[C:10]3=[N:14][CH:13]=2)=[O:16])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33]
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: C=CCOC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(Br)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a suspension of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (1.00 g, 2.02 mmol) and 1-amino-cyclopropanecarboxylic acid allyl ester hydrochloride (430 mg, 2.42 mmol) in 6 mL of DMF at room temperature was added diisopropylethylamine (1.05 mL, 6.06 mmol), and the reaction mixture (became mostly clear) was stirred for 10 min. HATU (845 mg, 2.22 mmol) was then added, and the clear yellow reaction mixture was stirred at room temperature for 21 h. The reaction mixture was partitioned between 150 mL of ethyl acetate and 50 mL of 1 M HCl. The organic phase was washed with satd. NaHCO3 solution, water (2×), and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (50 g, 10-30% EtOAc in hexanes), to furnish 1.16 g of 1-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (93%) as a colorless foam.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:3]1=2.[SH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38]>>[C:37]([CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:3]1=2)([OH:39])=[O:38]
Reactant: OC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-8-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)O)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[N:21]=[CH:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[CH:43](O)=[O:44]>CC(=O)OCC.O.[Zn]>[CH:43]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:32][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[N:21]=[CH:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])=[O:44]
Reactant: O=CO
Reactant: CC(C)c1ccccc1-c1ncc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 56 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-((4-chlorophenyl)(hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.0247 mmol) in HCOOH (1 mL) was added Zn dust (8 mg, 0.123 mmol). The reaction was heated at 50° C. for 1 h, cooled to RT then diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (7 mg, 56% yield) as a colorless oil. LCMS: MH+ 506 and TR=2.225 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([CH:19]=O)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Reactant: Nc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc3c(CNc4cccnc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde (100 mg, 0.376 mmol) was dissolved in 5 mL ethylendichloride. 3-Aminopyridine (50 mg, 0.532 mmol) and acetic acid (90 mg, 1.50 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (172 mg, 0.811 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 50 mL water. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from dichloromethane. The title compound was obtained as a white solid (50 mg, 39%), MS: m/e=345.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccccc2)c1O

Procedure:
A mixture of 6.69 g (24.7 mmol) of 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone, from the preceding example, 5.35 g (31.3 mmol) of benzyl bromide, 14.9 g (0.108 mol) of anhydrous potassium carbonate, 115 mL of dry N,N-dimethylformamide, and 230 mL of acetone was stirred and refluxed for 8 hr. After being cooled, the slurry was filtered with suction and the solids washed well with acetone. The filtrate and washes were combined and concentrated under reduced pressure to give a yellow oil which was chromatographed on silica gel. There was obtained 5.57 g (62.6%) of the desired monoether as a pale-yellow solid. Recrystallization of a sample from hexane-ethyl acetate gave the title compound as colorless needles, mp 115°-116° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])=[O:13].N>>[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:13])=[O:14]
Reactant: NC(=NO)c1cccnc1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(methylsulfonyl)benzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 3.24 (s, 3H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.89-7.96 (m, 1H), 8.28 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 8.55-8.61 (m, 2H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 8.78 (t, J=1.5 Hz, 1H), 9.32 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 302 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield N-(5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.6 (s, 1H), 8.18 (s, 2H), 7.8 (d, 1H), 7.62-7.77 (m, 2H), 7.42 (d, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:32][CH3:33])(=O)=O.O>CN(C)C=O>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH2:15]1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (1S,2S,3S,5R,6S)-3′-((allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid obtained below in Example A-1 (A-1-2, 200 mg) in N,N-dimethylformamide (6 mL), cesium carbonate (261 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl tosylate (201 mg) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed once with water and once with brine, sequentially, and then the ethyl acetate layer was dried over anhydrous sodium sulfate. The insoluble was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate=100:0-50:50) to give (1S,2S,3S,5R,6S)-3′-allyl 6-ethyl 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (Reference Example 1-1, 68 mg) as a colorless amorphous.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[NH:21]N.C(O)C.Cl>O>[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[N:21]1[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1cccnc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3nccc3-c3cccnc3)c(F)c2)C(=O)O1
Yield: 42.5 %

Procedure:
(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (58 mg, 0.327 mmol) and (S)—N-((3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (94 mg, 0.327 mmol) were combined with a solvent, ethanol (3 mL), and then the mixture was slowly heated to reflux, followed by addition of concentrated hydrochloric acid (40 μL). The reaction mixture was maintained under reflux until completion of the reaction as monitored by TLC. Then, the reaction mixture was poured into water and then was extracted with dichloromethane. The dichloromethane layer was rotary evaporated. The residue was purified with column chromatography to afford 55 mg light yellow solid, with a yield of 40.7%, melting point: 83.7-85.9° C., HPLC: 98.2%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4F)=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[O:47]1CCOC[CH2:48]1.[OH-].[K+].CO>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:34][CH2:35][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:38]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=4[O:47][CH3:48])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: C1COCCO1
Reactant: CCOC(=O)CCN[C@H]1CC[C@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of trans-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (Example 526) (0.04 g, 0.06 mmol), p-dioxane (4 mL), potassium hydroxide (0.02 g, 0.31 mmol), a trace amount of methanol and water (0.4 mL) were heated at 80° C. for 1 hour. The mixture was stirred at ambient temperature overnight and at 80° C. for 4 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield trans-3-({4-[4-amino-3-(3-methoxy-4-{[2-methoxy-4-trifluoromethylbenzoyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.04 g, 0.06 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.72 (s, 1H), 8.61(d, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 7.61(s, 1H), 7.53 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 4.20 (s, 3H), 4.05 (s, 3H), 1.44-3.61 (m, 13H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.36 min.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15]C(Cl)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]3[C@@H:40]2[CH2:39][C@H:38]([OH:45])[C@@:37]2([CH3:46])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]1.O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][NH:19][C@H:20]3[CH2:43][CH2:42][C@@:41]4([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]5[C@@H:40]4[CH2:39][C@H:38]([OH:45])[C@@:37]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NOCC5c6ccccc6-c6ccccc65)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (1.4 g; 5.4 mmol) in 1,4-dioxane (18 mL) was added dropwise to a suspension of (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid A (2.0 g; 4.9 mmol) (3) in 10% aq. Na2CO3 (30 mL) and 1,4-dioxane (18 mL) stirred at 0° C. After 6 h stirring at room temperature H2O (100 mL) was added, the aqueous phase washed with Et2O (2×90 mL) and then 2 M HCl (15 mL) was added (final pH: 1.5). The precipitated solid was filtered, washed with H2O (3×100 mL), vacuum dried and then purified by flash chromatography to give B as a white solid (2.2 g; 3.5 mmol). Yield 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:23][C:24](=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[S:18][CH:23]=[C:24]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:19]=3)[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CSc2cc(NC(N)=S)ncc2Br)cc1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)cc1
Temperature: 75 °C
Yield: 61 %

Procedure:
1-(4-(4-methoxybenzylthio)-5-bromopyridin-2-yl)thiourea (3.0 g, 7.8 mmol) and 1-bromo-4-phenylbutan-2-one (1.77 g, 7.8 mmol) were diluted in EtOH (120 mL). Triethylamine (2.2 ml, 15.6 mmol) was added, and the solution was heated at 75° C. for 3 hours. The solution was cooled and concentrated to half the amount of solvent. The solid was filtered and rinsed with cold EtOH to provide the desired product (2.44 g, 61% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[C:4]([CH3:23])[C:3]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)=[C:4]([CH3:23])[C:3]=2[CH3:24])=[CH:28][CH:27]=1
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 59.9 %

Procedure:
Heat a mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.5 g, 4.23 mmol), 4-fluorophenylboronic acid (887 mg, 6.34 mmol), Cs2CO3 (5.51 g, 16.9 mmol) and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (29 mg, 0.042 mmol) in a mixture of 1,4-dioxane (30 mL) and H2O (10 mL) under N2 at 90° C. overnight. Partition the reaction mixture between H2O and CH2Cl2. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a white foam (1.05 g, 60%). ES/MS m/z 415.2 (M+1).