Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[C:12]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=[C:10]([CH3:24])[C:9]=1[CH3:25])(=[O:3])[CH3:2].[H][H]>[Pt].C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([CH3:25])=[C:10]([CH3:24])[N:11]=[C:12]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1N

Procedure:
1-[(2,3-Dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]eth-2-yl acetate (11.5 g, 33.30 mmol) was combined with 5% platinum on carbon (5.0 g) in a Parr flask. Toluene was added to the flask (120 mL) and the resulting mixture was pressurized with hydrogen at 310 kPa at room temperature for 1.6 hours. The reaction was complete as determined by LC/MS and HPLC. The resulting reaction mixture was filtered through Celite™ filter agent, and the filter cake was rinsed with more toluene. The volatiles were removed under reduced pressure, and the resulting oil was carried on to the next step.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@:4]([CH3:38])([CH2:19][CH:20]1[CH2:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[CH3:37])[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[OH-].[Li+]>O1CCOCC1.O>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@:4]([CH3:38])([C:3]([OH:39])=[O:2])[CH2:19][CH:20]1[CH2:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]1[CH3:37])=[O:7])[CH2:11]2
Reactant: COC(=O)[C@](C)(CC1CN=C(c2ccccc2)c2ccccc2N1C)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1c2ccccc2C(c2ccccc2)=NCC1C[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O

Procedure:
To a stirred solution of N-[(2-adamantyloxy)carbonyl]-β-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-yl )-α-methyl-alanine methyl ester (diastereomeric mixture, 5.3 g, 10 mmol) in a mixture of 150 mL dioxane and 75 mL water was added lithium hydroxide (0.72 g, 30 mmol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:7][C@H:8]([C:13]([NH2:15])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11].C(=O)([O-])[O-].[K+].[K+].N[C@H](C(N)=O)CC(=O)N>O.C(OCC)C>[C:1]([NH:15][C:13](=[O:14])[C@H:8]([CH2:9][C:10](=[O:12])[NH2:11])[NH2:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: NC(=O)C[C@H](N)C(N)=O
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=CC(=O)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 0.17 h

Procedure:
A 5 ml portion of acrylic acid chloride and 200 ml of diethyl ether were put into a 500 ml capacity eggplant type flask and stirred on an ice bath. Next, 1.84 g of asparagineamide hydrochloride (mfd. by Kokusan Kagaku) was dissolved in 40 ml of deionized water, and 3 g of potassium carbonate was dissolved in 20 ml of deionized water. The asparagineamide aqueous solution was mixed with the potassium carbonate aqueous solution. The mixed liquid was added dropwise into the eggplant type flask spending 10 minutes while stirring constantly, and the mixture after completion of the dropwise addition was stirred for 24 hours. Diethyl ether layer in the thus obtained reaction liquid was discarded, and the water layer was concentrated at 25° C. under a reduced pressure. One liter of acetone was added to the thus obtained residue and stirred for 1 hour. The insoluble solids were removed by suction filtration. By recrystallizing from the acetone layer, 0.5 g of colorless crystals were obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][CH3:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC)OCC3
Yield: 62.5 %

Procedure:
To a solution of compound 1 (348 mg, 1.27 mmol) in dry THF (5 mL) under argon, 60% NaH in mineral oil (64 mg, 1.59 mmol, 1.25 eq) was added in a portion-wise manner. After stirring for thirty minutes, MeI (99 μL, 1.59 mmol, 1.25 eq) was added dropwise, and the reaction was stirred for 2 days at room temperature. The resulting mixture was diluted with brine and extracted three times with Et2O. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow-white solid (228 mg, 62%): mp 125–126° C. 1HNMR (CDCl3, δ TMS): 0.86 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.15 (m, 2H), 2.78 (t, 2H), 2.85 (q, 2H) 3.37 (s, 3H), 3.52 (m, 2H), 4.00 (m, 2H), 6.99–7.38 (m, 3H, Ar—H), 8.43 (br, 1H, NH). MS−: m/z 286 ([M−H]−). Anal. (C18H25NO2): C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])(=[NH:14])=[O:13]>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)c1cccc(S(C)(=N)=O)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1

Procedure:
In a manner similar to that described in Example 480 (step 6), 5-bromonicotinic acid and methyl 3-(S-methylsulfonimidoyl)benzoate were reacted to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Agent: N
Solvent: CO
Solvent: O
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Temperature: 40 °C
Yield: 98.4 %

Procedure:
A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.2 g of water wet Raney nickel #30. The solution is heated at 40° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.13 g of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro-[5.5]undecane-2-acetic acid.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][C@H:15]1[C:20](=[O:21])[C@H:19]([CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:18]2[CH2:33][C@H:16]1[C:17]2([CH3:35])[CH3:34]>C1COCC1>[OH:13][C:9]1[CH:8]=[C:7]([C@@:20]2([OH:21])[C@H:19]([CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@H:18]3[CH2:33][C@@H:16]([C:17]3([CH3:34])[CH3:35])[C@H:15]2[CH3:14])[CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H]1C(=O)[C@H](CN(C)CCc2ccccc2)[C@@H]2C[C@H]1C2(C)C
Reactant: Oc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H]([C@@H](CN(C)CCc3ccccc3)[C@]1(O)c1cccc(O)c1)C2(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
Add a solution of t-BuLi (20 mL, 26.0 mmol) via syringe to a solution of 3-bromo-phenol (2.06 g, 12 mmol) in THF (20 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add a solution of (1R,2R,4S,5S)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-one (2.99 g, 10 mmol) in THF (2 mL) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the aqueous mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by Preparative HPLC to give (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol as pale yellow oil (0.27 g, yield: 6.9%), MS (m/z): 394 (M+1).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCOCc1ccccc1
Reactant: NS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)NCCCOCc1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To a solution of sulfamide (1.0 g, 10.4 mmol) in dry DMF (50 mL) is added NaH (416 mg 60% dispersion in mineral oil, 10.4 mmol) in portions. After the evolution of gas has stopped, (3-bromo-propoxymethyl)-benzene (2.38 g, 10.4 mmol) is added and the reaction mixture is stirred at 50° C. for 18 h. The suspension is cooled to rt, neutralized with 1N aq. HCl (5 mL) and concentrated. The solid residue is suspended in acetone and filtered. The filtrate is evaporated and the residue is purified by column chromatography on silica gel eluting with hexane/EA to afford 3-benzyloxypropylsulfamide (651 mg) as a colourless oil. LC-MS: tR=0.73 min, [M+H]+=245.18; 1H NMR (CDCl3): δ 7.39-7.27 (m, 5H), 4.94 (t br, J=4.6 Hz, 1H), 4.53 (s br, 2H), 4.50 (s, 2H), 3.60 (t, J=5.9 Hz, 2H), 3.26 (q, J=5.9 Hz, 2H), 1.89 (p, J=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([CH:15]=[C:16]([C:22]([O-])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>C(O)C>[CH2:20]([O:19][C:17]([CH:16]1[C:22](=[O:23])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH:15]1[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:26][CH:25]=1)=[O:18])[CH3:21]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1)C(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1C(=O)Nc2ccccc2SC1c1ccc(OC)cc1
Yield: 27.4 %

Procedure:
A mixture of 32 g of o-aminothiophenol, 69.6 g of ethyl p-methoxybenzalmalonate and 1.6 g of triethylamine hydrochloride was heated at about 180° C. until no further ethanol was distilled out (for about 4 hours). The resulting mixture was then worked up in the same manner as described in Reference Example 2 (a) and the crystals thus obtained were recrystallized from chloroform-petroleum ether to obtain 25 g of 2,3-dihydro-3-ethoxycarbonyl-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 192° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: CCNC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Yield: 58 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using ethylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (42 mg, 58%) which was obtained as a white solid. MS: m/e=361.2 [M+H]+.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[CH3:18][C:19]12[CH2:29][C:23]3([OH:30])[CH2:24][C:25]([OH:28])([CH2:27][C:21]([CH3:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[CH3:31][C:21]12[CH2:27][C:25]3([OH:28])[CH2:24][C:23]([O:30][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:29][C:19]([CH3:18])([CH2:26]3)[CH2:20]1)[CH2:22]2
Reactant: CC12CC3(C)CC(O)(C1)CC(O)(C2)C3
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3(C)CC(C)(CC(O)(C3)C1)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1,3-dimethyl-5,7-dihydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1,3-dimethyl-5-hydroxy-7-acryloyloxyadamantane (yield: 87%, white solid) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24]>>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CCNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 77.1 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 900 mg (4 mmol) of 3′-ethylaminobiphenyl-4-carbaldehyde with 470 mg (4 mmol) of 2,4-thiazolidine dione, 1 g (77%) of the expected product are obtained in the form of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cccc3ccccc23)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-naphthalene using the conditions described in Example 10C to provide 1-(4-Chloro-3-nitro-phenoxymethyl)-naphthalene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)O)cn1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 2-(6-methoxypyridin-3-yl)-2-(phenylamino)acetic acid (I1) (100 mg, 0.39 mmol), (R)-quinuclidin-3-ol (59.1 mg, 0.46 mmol), HOBT (71.2 mg, 0.46 mmol) and DCC (96 mg, 0.46 mmol) was dissolved in dry THF (10 ml). The resulting reaction was stirred at room temperature overnight. Then solvent was removed under reduced pressure, and the residue was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(6-methoxypyridin-3-yl)-2-(phenylamino)acetate (33 mg, 23% yield).
Reaction SMILES: [C:1]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:3](=[O:10])[CH2:2]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:2][C:3]2=[O:10])([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CC2(CCCC2)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CC2(CCCC2)c2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 9210.9 %

Procedure:
To a chilled solution of spiro(cyclopentane-1,1'-indan)-3'-one (16.7 g; 0.09 moles) in conc. sulphuric acid (100 ml) there are added in portions under agitation a solution of potassium nitrate (10 g) in conc. sulphonic acid (30 ml). The temperature should not exceed 10°-15° C. The mixture is kept cold for 1 hour and then put on ice. The crude product is sucked off and thoroughly washed with water. After drying there are obtained 1917 g of a yellow powder (yield 95%), mp. 104° C. A sample is recrystallized from N-hexane and melts at 110° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=O>O>[F:1][C:2]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:3]=1[O:4][CH2:5][CH2:6][C:7]2=[O:9]
Reactant: Cc1ccc(F)c(OCCC(=O)O)c1
Solvent: O
Product: Cc1ccc(F)c2c1C(=O)CCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
A mixture of 3-(2-fluoro-5-methylphenoxy)propanoic acid (2.45 g, 12.4 mmol, STEP 1-1) in polyphosphoric acid (35 g) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (150 mL), and extracted with ethyl acetate (60 mL×2). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuum to afford the title compound as a white solid (2.30 g, quant.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[C-:14]#[N:15].[Na+].O>CN(C=O)C>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution containing 2.085 g (8.18 mmol) of 4-trifluoromethoxybenzyl bromide in 10 mL dry DMF was added 441 mg (8.99 mmol) of sodium cyanide. The reaction was stirred for 1 h at room temperature, poured into water and extracted with of ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was used in the next reaction without further purification.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][C:21]([OH:23])=[O:22]>ClCCl>[C:21]([CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)([OH:23])=[O:22]
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: O=C(O)CS
Solvent: ClCCl
Product: O=C(O)CSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (305 mg) was dissolved in dichloromethane (10 ml) and mercaptoacetic acid (0.07 ml) was added. The solution was stirred at room temperature for 3 days, during which time a yellow precipitate was formed, which was filtered off and recrystallised from absolute ethanol to give 10-(carboxymethylthio)-1,8-dihydroxy-9-anthrone (237 mg, 75%) as yellow needles, melting point 151°-152° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23](C)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc2c(-c3ccccc3F)nn(C3CCCCO3)c2cn1
Product: Fc1ccccc1-c1n[nH]c2cnc(-c3cncnc3)cc12
Yield: 25 %

Procedure:
Following the procedures as described in Example 136, pyrimidin-5-ylboronic acid and 3-(2-fluorophenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 138 as a white solid (25 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 14.2 (s, 1H), 9.51 (s, 2H), 9.28 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 7.92 (mt, 2H), 7.59 (t, 2H), 7.41 (t, 1H). ESI MS m/z=292 (M+1)
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:15][C:14]([O:13][CH3:12])=[O:35])=[CH:4][CH:5]=1)([OH:9])=[O:8]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 4-formylbenzoic acid (1.00 g) in dry tetrahydrofuran (15 ml) was added methyl(triphenylphosphoranylidene)acetate (2.50 g) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 hour at the same temperature, poured into aqueous sodium bicarbonate solution, and washed with ethyl acetate. 1N-Hydrochloric acid was added to the aqueous layer until the layer was adjusted to pH 2. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl 4-carboxycinnamate (1.21 g) as colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Cl[C:40]([F:47])([F:46])C(OCC)=O>CCOC(C)=O>[F:46][CH:40]([F:47])[O:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(O)cn3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(OC(F)F)cn3)cc2)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
(R)-tert-Butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.24 g) and K2CO3 (124 mg) were combined with DMF (2 ml) to give a brown solution. Ethyl 2-chloro-2,2-difluoroacetate (152 mg) was then added. The reaction mixture was stirred at 80° C. for 1.5 h to afford a dark brown suspension. TLC & HPLC showed the reaction was complete. The reaction mixture was poured into EtOAc and washed sequentially with water and with saturated brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (60 mg, 24%) as a yellow oil. MS (ISP): 423.1 ([M+H]+), 367.0 ([M+H—C4H8]+).