Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:39])(C)(C)C>ClCCl>[CH3:39][C:17]1[CH:18]=[C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])[CH:20]=[CH:21][C:16]=1/[CH:15]=[CH:14]/[C:13]([OH:40])=[O:12]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of (E)-3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-acrylic acid tert-butyl ester from Example E45.2 (338 mg, 0.76 mmol) in dichloromethane (10 ml) and the mixture was stirred for 45 min at room temperature. Solvents were removed in vacuo and azeotroped with dichloromethane to yield the title compound (337 mg, 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1)=[O:2].C[O-].[Na+].S([CH2:26][N+:27]#[C-:28])(C1C=CC(C)=CC=1)(=O)=O>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)=[CH:28][N:27]=[CH:26]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(C=O)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(-c2cnco2)nc1

Procedure:
To a suspension of methyl 6-formylnicotinate (60 mg, 0.363 mmol) in methanol (3 mL) was added sodium methoxide in methanol (0.5M, 2.91 mL, 1.45 mmol). Tosylmethyl isocyanide (85 mg, 0.436 mmol) was added to the reaction and the mixture was heated at reflux overnight. After cooling, the reaction mixture was concentrated. The residue was treated with 5% citric acid/50% brine (1:1) and extracted with ethyl acetate. The suspension was filtered, washed with water, and dried under vacuum to provide the title compound. MS (DCI/NH3) m/z: 191.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]C)=[O:12])=[CH:9][N:10]=2)[CH:7]=1.O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cnc2ccc(Br)cn12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2ccc(Br)cn12
Yield: 93.1 %

Procedure:
Reaction mixture containing N′-(5-bromopyridin-2-yl)-N,N-dimethylformimidamide (6.5 g, 28.5 mmol), methyl 2-bromoacetate (5.6 g, 3.5 mL, 37.0 mmol) and NaHCO3 (4.1 g, 48.8 mmol) in i-PrOH (60 mL) was heated at 90° C. under nitrogen. The heating was stopped after 12 h and cooled the dense heterogeneous reaction mixture to room temperature. The reaction mixture was concentrated and diluted with water. The resultant slurry was collected by suction filtration and obtained methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (6.9 g) as a tan white solid upon drying. 1H NMR (300 MHz, DMSO-d6): δ 9.31 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.71 (dd, J=9.5, 1.6 Hz, 1H), 3.88 (s, 4H). Ester hydrolysis was done by stirring a solution of methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.5 g), LiOH.H2O (1.2 g) in THF/MeOH/H2O (1/1/1, 75 mL) at room temperature. Reaction mixture was concentrated upon complete hydrolysis of ester to corresponding acid, diluted with water/ice and acidified with 2N. aq HCl until pH 6. The resulting solid was filtered, suction dried followed by drying under P2O5 under vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (2.2 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.N([O-])=O.[Na+].[Na+].[I-:29]>Cl.O>[I:29][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: [I-]
Reactant: Nc1ccc(-n2ccccc2=O)cc1OCCN1CCCCC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1ccccn1-c1ccc(I)c(OCCN2CCCCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a solution of 1-(4-amino-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.44 g, 1.08 mmol) in conc. HCl (3 mL) at 0° C., a solution of NaNO2 (75 mg, 1.08 mmol) in H2O (2 mL) was added dropwise. After 30 min of stirring at 0° C., NaI (0.76 g, 5.07 mmol) in H2O (2 mL) was added. After being stirred at 0° C. for 30 min, the mixture was removed to room temperature and was stirred at room temperature for 4 h. The solution was basified with 5 N NaOH to pH 10-12. The product was extracted with EtOAc, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:13]C(=O)N[C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-:18].[Na+]>>[ClH:1].[NH2:13][C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:16])[C:10]([OH:18])=[O:15]
Reactant: [OH-]
Reactant: CC1(c2ccc(Cl)c(Cl)c2)NC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Product: CC(N)(C(=O)O)c1ccc(Cl)c(Cl)c1
Yield: 27 %

Procedure:
A solution of 5-(3,4-dichloro-phenyl)-5-methyl-imidazolidine-2,4-dione (3.0 g; CAS 52715-57-8) in 3N NaOH (30 ml) was refluxed overnight. The reaction mixture was cooled to 0°, then brought to pH 1 by dropwise addition of concentrated HCl. The resulting white slurry was filtered. The solid was washed extensively with H2O, dried in the vacuum, resuspended in EtOH (25 ml), collected by filtration, washed with EtOH and diethylether and dried in the vacuum to give (RS)-2-amino-2-(3,4-dichloro-phenyl)-propionic acid hydrochloride (1.35 g, 27%) as off white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7](=[O:20])[NH:6]1)=O.[Li+].[BH4-]>CO>[OH:2][CH2:3][CH:5]1[NH:6][C:7](=[O:20])[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: COC(=O)C1NC(=O)c2ccccc2-c2ccccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: O=C1NC(CO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-5-carboxylic acid methyl ester (120 mg, 0.45 mmol) in MeOH (5 mL) at 0° C. is added LiBH4 (20 mg, 0.9 mmol). The mixture is allowed to warm to RT and stirred there for 18 h. Additional LiBH4 is added until starting material is consumed. The solvent is removed under reduced pressure and water is added. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[CH2:15]=[O:16]>>[OH:16][CH2:15][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[C:3]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Cc1[nH]c(=O)ccc1-c1ccncc1
Reactant: C=O
Product: Cc1[nH]c(=O)c(CO)cc1-c1ccncc1

Procedure:
The reaction of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is carried out by heating the reactants at about 75° to 125° C. It is preferably run using an acidic pH of about 2 to 5, a large molar excess of formaldehyde and a reaction temperature of about 90° to 110° C. The quantity of formaldehyde can vary widely provided it is in excess of said 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone. In practice, a large excess, e.g., from about 10-fold to 100-fold or greater can be used; however, as little as a 2-fold excess or less of formaldehyde can be used although the reaction time is longer. Because of its ready availability and low cost, 37% aqueous formaldehyde solution is preferred.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81](Br)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:30])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 23.8 %

Procedure:
(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.10 g, 0.24 mmol), bis(pinacolato)diboron (0.073 g, 0.29 mmol), Palladium dichloride(dppf) (0.018 g, 0.024 mmol), and potassium acetate (0.071 g, 0.72 mmol) were suspended in 1,4-dioxane (1.2 mL) and degassed with argon for 30 minutes. The suspension was heated at 85° C. for 2 hours. The mixture was cooled, (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.182 g, 0.346 mmol) and aqueous potassium phosphate (2M, 0.84 mL, 0.84 mmol) was added. The mixture was returned to heat for 16 hours at which time, Palladium(tetrakis)triphenylphosphine (0.014 g, 0.012 mmol) was added. The reaction was heated for an additional 4 hours. Upon completion, the crude reaction mixture was concentrated in vacuo and filtered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE). The resulting slurry was diluted in DMF and purified by reverse phase HPLC (15-40% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [1-(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.048 g, 24%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:34])[CH:12]=2)[CH:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[F:34][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:15]=[C:14]2[C:16](=[O:33])[C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(C(=O)c3cc(CC(=O)O)cc4ccc(F)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To a stirred solution of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.05 g, 0.10 mmol) in tetrahydrofuran (6 mL) was added a solution of lithium hydroxide monohydrate (0.021 g, 0.50 mmol) in water (1.5 mL) and the reaction mixture was stirred for 48 hours at room temperature. The solvents were distilled off under reduced pressure, then the residue was diluted with water (4 mL) and washed with ethyl acetate (2×3 mL) to remove unwanted organic products. The aqueous layer was separated and acidified to pH ˜3-4 with a 1.0 N aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.020 g (42%) of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.19 (m, 2 H), 7.84-8.05 (m, 5 H), 7.71 (s, 1 H), 7.48-7.61 (m, 1 H), 3.81 (s, 2 H), 2.97 (br. s, 4 H), 2.38 (br. s, 4 H), 2.15 (s, 3 H). MS cald. for C24H23FN2O5S ([M+H]+) 471, obsd. 471.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:9][N:10]([CH2:18][CH2:19][NH:20][CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][N:10]([CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: Cc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cncc(N(C)CCN(C)C(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-methylpyridine (350 mg, 2.035 mmol), tert-butyl N-methyl-N-(2-methylaminoethyl)carbamate (686 mg, 3.05 mmol), RuPhos (47.5 mg, 0.102 mmol) and sodium tert-butoxide (489 mg, 5.09 mmol) were combined in anhydrous toluene (15 ml). The mixture was purged with argon, tris(dibenzylideneacetone)dipalladium (0) chloroform complex (105 mg, 0.102 mmol) was added and the mixture was stirred at 100° C. overnight. The mixture was filtered through kieselguhr, concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient of 10 to 50% ethyl acetate in heptane) to yield 301 mg (1.078 mmol, 53%) MS(ESI) m/z=280.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.[ClH:20].O1CCOCC1.CO>C(OCC)C>[ClH:20].[ClH:20].[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: Cc1ncsc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ncsc1N1CCNCC1
Yield: 86.8 %

Procedure:
To a solution of tert-butyl 4-(4-methylthiazol-5-yl)piperazine-1-carboxylate (265 mg, 0.935 mmol) in diethyl ether (10 mL) was added HCl (4N in dioxane, 4.5 mL, 18 mmol) after which a precipitate formed immediately. 1,4-Dioxane (5 mL) was added to dissolve the precipitate. The mixture was stirred at room temperature for three days after which additional HCl (4N in dioxane, 5 mL, 20 mmol) and methanol (5 ml) was added. Stirring was continued for another day, the precipitate formed was collected by filtration, washed with diethylether and dried under reduced pressure to yield 208 mg of a yellow solid (0.812 mmol, 87%). MS (ESI) m/z=184.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1([C:20]([OH:22])=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC>>[OH:1][C@@:2]1([C:20]([OH:22])=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1
Reactant: COc1ccc(OC)c2c1CC(O)(C(=O)O)CC21SCCS1
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Product: COc1ccc(OC)c2c1C[C@](O)(C(=O)O)CC21SCCS1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A suspension of 3.42 g of rac-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylic acid [prepared as described in Example 4(iii)] and 4.0 g of brucine was heated under reflux until a clear solution was obtained. After seeding, the solution was left to cool slowly to room temperature. The crystalline precipitate (3.6 g) was collected after 2 days. The precipitate was dissolved in 1500 ml of boiling ethyl acetate, the solution was concentrated to 600 ml and left to cool slowly. The crystalline product [2.7 g [α]D20 =-46.6°, c=0.5% in dimethylformamide] was suspended in 150 ml of ethyl acetate and shaken with three 10 ml portions of 5-M hydrochloric acid and with two 100 ml portions of brine. After drying over magnesium sulphate, the solvent was evaporated to give a colourless oil which was crystallised from diethyl ether to yield 1.22 g of (R)-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylic acid in the form of colourless crystals of melting point 147° -149° C.; [α]D20 =+13.8°, c=0.5% in dioxan.
Reaction SMILES: [C:1]([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7]1)(=O)[CH:2]([CH3:4])[CH3:3].B.C1COCC1.Cl.O>O1CCCC1>[CH2:1]([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:21])(=[O:22])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Yield: 65.7 %

Procedure:
To a solution of 4-isobutyryl-5(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3.2-f]-1,4-thiazepine-1,1-dioxide (1.009 g, 2.75 mmol) in dry tetrahydrofuran (30 mL), under an inert atmosphere was added 1M borane·THF (9 mL, 9.0 mmol) and the reaction mixture was refluxed for three hours. Concentrated HCl and water were then added to the cooled reaction mixture. After refluxing this mixture for 0.5 hours, the solvent was removed, the residue was made basic with NaHCO3 and the product was extracted into ethyl acetate. The extract was dried (Na2SO4), filtered and the solvent evaporated. Trituration of the residue with diethyl ether and n-butyl chloride gave 637 mg (65%) of crystalline product. Recrystallization of the solid from diethyl ether twice afforded analytically pure title compound (446 mg), mp 125°-127° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H].C>CO.O=[Pt]=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: COCc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: COCc1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 1-(methoxymethyl)-2-nitrobenzene (4.30 g, 25.7 mmol) and PtO2 (0.29 g, 1.29 mmol) in MeOH (30 mL) was charged with 1 atmosphere hydrogen and stirred at ambient temperature for 1 hour. Charcoal (5 g) was added and the reaction mixture was stirred for 10 minutes. The solid was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure to give 2-(methoxymethyl)aniline (3.42 g, 96.9%) as a solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([O:34]C)=[O:33])[CH:22]=3)[O:17]2)[CH2:13][CH2:12]1)=[O:10])[CH3:4]>CO.C1COCC1>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([OH:34])=[O:33])[CH:22]=3)[O:17]2)[CH2:13][CH2:12]1)=[O:10])[CH3:4]
Reactant: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)OC)c4)ccc2O3)cc(OC)c1-c1cnn(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OC)c1-c1cnn(C)c1
Temperature: 25 °C

Procedure:
Aqueous 1 N sodium hydroxide solution (0.75 mL) was added to a solution of Methyl 5-{1′-[3-ethoxy-5-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate in MeOH (2 ml) and THF (2 ml) and stirred at room temperature for over night. The organic solvent was evaporated and diluted with water. Aqueous 1N HCl aq. (1 ml) was added thereto at room temperature, and the resulted solid was collected and recrystallized from MeOH to afford the intended compound as a colorless solid. 1H-NMR (DMSO-d6) δ: 9.08 (1.0H, d, J=2.2 Hz), 9.02 (1.0H, d, J=1.7 Hz), 8.41 (1.0H, dd, J=2.2, 1.7 Hz), 8.07-8.03 (3.0H, m), 7.88 (1.0H, d, J=0.5 Hz), 7.27-7.24 (1.0H, m), 6.72-6.70 (2.0H, m), 4.33-4.19 (1.0H, br m), 4.09 (2.0H, q, J=7.0 Hz), 3.85 (3.0H, s), 3.83 (3.0H, s), 3.67-3.11 (3.0H, br m), 2.94 (2.0H, s), 2.12-1.89 (2.0H, br m), 1.84-1.77 (2.0H, m), 1.37 (3.0H, t, J=7.0 Hz). MS [M+H]+=597.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43].[CH:44]([OH:47])([CH3:46])[CH3:45]>CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18]([O:47][CH:44]([CH3:46])[CH3:45])[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(OC(C)C)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Dry iso-propanol (2 mL) was treated with NaH (0.00612 g, 0.153 mmol, 60% in mineral oil) under argon and stirred for 10 min. The product of Example 23d, N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.070 g, 0.120 mmol) was added in iso-propanol (2 mL). The reaction was stirred under argon for 1 hour and then warmed to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc and the organics washed with water, brine (twice), dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel, eluting with a CH2Cl2 −10% EtOAc/CH2Cl2 gradient to afford the title compound as a white solid. mp 253.5-255.4° C.; LC-MS m/z 562 (M+H)+, 2.44 min (ret. time).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:2]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccccc1Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3Cl)(CC1)CC2

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-chloroaniline (35.8 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(2-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (17.4 mg).