Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:26]\[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1ccc(/C=C(/C(=O)OC(C)(C)C)C(=O)c2ccccc2O)cc1
Yield: 69 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (354 mg, 1.5 mmol), p-tolualdehyde (150 μL, 1.5 mmol), 15.0 mL benzene, piperidine (15 μL, 0.15 mmol) and glacial acetic acid (8.6 μL, 0.15 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 350 mg (69%) of clear prisms. mp=86-89° C.; IR (film) 2978.2; 1712.8; 1624.5; 1155.2 cm−1; 1H NMR (100.7 MHz, CDCl3) δ 11.93 (bs, 1H), 7.82 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.2 Hz, 1H), 7.25-7.08 (AA′BB′, 4H), 7.03 (d, J=8.2 Hz, 1H), 6.81 (t, J=7.6 Hz, 1H), 2.30 (s, 3H), 1.40 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 202.0, 163.9, 162.8, 142.3, 141.3, 137.1, 131.9, 130.4 (x2), 130.1, 129.9, 120.2, 119.5, 118.4, 82.6, 28.1, 21.6; LRMS (electrospray): Mass calculated for C21H22O4, [M]+, 338.14. Found [M+23]+, 361.4.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:32]3[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])[CH:35]=[CH:36][CH:37]=3)=[C:11]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])=[O:19])[C:12](=[O:16])[O:13]2)=[CH:8][C:7]=1[CH3:43].C(O)C.[NH3:47]>O>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:32]3[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]([O-:42])=[O:41])[CH:35]=[CH:36][CH:37]=3)=[C:11]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:29])([F:31])[F:30])=[O:19])[C:12](=[O:16])[O:13]2)=[CH:8][C:7]=1[CH3:43].[NH4+:47]
Reactant: N
Reactant: Cc1cc2c(-c3cccc(/C=C/C(=O)O)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc2c(-c3cccc(/C=C/C(=O)[O-])c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Product: [NH4+]
Temperature: 60 °C

Procedure:
A mixture of (2E)-3-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}acrylic acid acetone solvate (60 g), ethanol (540 ml) and water (108 ml) was heated to 60° C., and 5% aqueous ammonia (54 ml) was added dropwise thereto with stirring to dissolve the mixture. The solution was stirred at about the same temperature for 30 minutes and, after filtration, the solution was washed with a mixture of ethanol (60 ml) and water (12 ml). The filtrate was combined with the washings to obtain a solution of ammonium (2E)-3-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}acrylate. The solution was warmed to 75° C., and an aqueous solution of calcium chloride (5.9 g/120 ml) was added dropwise thereto with keeping the temperature almost the same and stirring. The reaction mixture was heated to 78° C., and stirred at about the same temperature for 3 hours and then at 25° C. for 1 hour. Crystals were collected by filtration, washed with ethanol/water (120 ml/120 ml), dried and stored at room temperature to obtain the title compound as colorless crystals (49 g, yield 80.1%). The crystals obtained showed the X-ray powder diffraction pattern as shown in FIG. 2 and have the following representative lattice spacings. Crystallinity was 75%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:67])([F:66])[F:65])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH2:58]>ClCCl>[CH3:51][C:52]1[O:53][C:54]([C:59]2[CH2:63][C:62]([C:68]3[CH:73]=[C:72]([Cl:74])[C:71]([Cl:75])=[C:70]([Cl:76])[CH:69]=3)([C:64]([F:66])([F:65])[F:67])[O:61][N:60]=2)=[CH:55][C:56]=1[CH2:57][NH:58][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CN
Reactant: O=C(O)C1CCOC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CCOC1
Reaction time: 24 h
Yield: 76.9 %

Procedure:
Tetrahydro-furan-3-carboxylic acid (81 mg), PyBOP (268 mg) and DIPEA (0.244 ml) are added to a solution of C-{2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methylamine (200 mg) in dichloromethane (4 ml). After 24 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield tetrahydro-furan-3-carboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (189 mg, compound 2.3 in Table 2) as a white foam. MS (HPLC/MS): 525 (MH+). Retention time: 1.97 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH2:17]1.Cl.O[NH:32][C:33](=[NH:35])[CH3:34].ClCCl.O>CN(C=O)C>[CH3:34][C:33]1[N:35]=[C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH:18]2[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH2:17]2)[O:25][N:32]=1
Reactant: O=C(O)c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: CC(=N)NO
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2C2CCN(CCc3ccccc3N3CCCCC3=O)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)benzoic acid a6-6 (0.31 g, 0.79 mmol, 1 eq) is dissolved in DMF and N,N′-carbonyldiimidazole (140 mg, 0.87 mmol, 1.1 eq) is added. The mixture is stirred at room temperature for 30 min, N-hydroxyacetamidine hydrochloride (95 mg, 0.87 mmol, 1.1 eq) is added and stirring is pursued for 4 hours. Another 1.1 eq of N,N′-carbonyldiimidazole and 1.1 eq of N-hydroxyacetamidine hydrochloride are added and the reaction mixture is stirred at reflux overnight. Dichloromethane and water are added and the organic layer is subsequently washed with water, HCl 1N, aqueous saturated NaHCO3 and brine. The organic layer is dried over MgSO4, evaporated and purified by preparative basic LC/MS (gradient: H2O/acetonitrile/NH4HCO3 0.5% w/v from 85/5/10 to 5/95/0 in 6.5 minutes) to afford 19 mg of 1-[2-(2-{3-[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 11.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([OH:12])=O)[CH2:6][C@H:5]([CH3:13])[O:4]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:10](=[O:12])[CH2:9][N:7]1[CH2:6][C@H:5]([CH3:13])[O:4][C@H:3]([CH3:2])[CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)O1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: C[C@@H]1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C[C@H](C)O1
Yield: 34.5 %

Procedure:
Proceeding as in Example 1, but substituting 2-((2R,6S)-2,6-dimethylmorpholino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 234, (S)-3-(benzyloxy)-2-(2-((2R,6S)-2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (14.8 mg, 34.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.99 (d, 1H), 7.60 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.73 (m, 2H), 3.55 (m, 2H), 2.98 (d, 2H), 2.77 (d, 1H), 2.71 (d, 1H), 1.76 (dd, 2H), 1.02 (d, 3H), 0.98 (d, 3H). MS (EI) for C30H34FN3O5. found 536.6 (MH+).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (8 g, 35 mmol), (EP 0307777 A2), and platinum(IV)oxide (174 mg) in ethanol (100 ml) and ethyl acetate (70 ml) was stirred under hydrogen at 1.3 atmospheres pressure for 1.5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (7/3) to give 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (6.56 g, 94%) as an oil which crystallised.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.O.[NH2:16][NH2:17].O1CCOCC1>O>[NH:16]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:17]
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)n(-c2ccc(NN)nn2)n1

Procedure:
A mixture of 34.2 g. of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 100 ml of 72% hydrazine hydrate and 200 ml of dioxane is stirred at 90°-95° C. for 14 hours, then the mixture is poured into 1 liter of water, extracted three times with 150 ml of chloroform each, and the combined organic phases are dried over magnesium sulphate. After evaporation of the solvent, the residue is recrystallized from isopropanol. Yield: 27 g /80%/; m.p.: 142°-143° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([Cl:13])=[CH:7][N:6]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[Cl:13][C:8]1[C:9]([C:11]#[N:12])=[CH:10][C:5]([S:3][CH2:1][CH3:2])=[N:6][CH:7]=1.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([S:3][CH2:1][CH3:2])=[CH:7][N:6]=1
Reactant: N#Cc1cc(Cl)ncc1Cl
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCSc1cc(C#N)c(Cl)cn1
Product: CCSc1cnc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.5 %
Yield: 18 %

Procedure:
A solution of 2.77 g of ethanethiol in 30 ml of 2-propanol was added to a mixture containing 7.7 g of 2,5-dichloro-4-pyridinecarbonitrile and 3.08 g of K2CO3 in 60 ml of 2-propanol at 0° C. The reaction mixture was allowed to warm to room temperature and then stirred for 4 days, after which it was poured onto 200 g of ice, stirred and extracted with CH2Cl2. Thin layer chromatography (using 10 percent ethyl acetate in hexane) disclosed the presence of three components. The CH2Cl2 solution was dried and concentrated to 25 ml and then diluted with 12.5 ml of hexane to give a crystalline material which was separated by filtration and identified as 2-chloro-5-ethylthio-4-pyridinecarbonitrile. The filtrate was concentrated and separated on a Water's Prep LC 500 instrument eluted with 2 percent ethyl acetate in hexane. Cuts of identical components were combined, evaporated and recrystallized to give 0.94 g (18%) of 5-chloro-2-ethylthio-4-pyridine-carbonitrile, (m.p. 103°-104° C.) and 3.33 g (64.5%) of 2-chloro-5-ethylthio-4-pyridinecarbonitrile (m.p. 112°-114° C.). The third component was identified as unreacted starting material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+].O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 32.7 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2% purity; 7.16 g (29.1 mmol)) was added gradually so that the internal temperature did not exceed −15° C. 10% Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed twice with water (48 ml), concentrated under a reduced pressure, crystallized with dichloromethane (18 ml) and acetone (120 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.56 g) (HPLC purity 99.7%, yield 32.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: CCCCCCOc1ccc(-c2cnc(Cl)nc2)cn1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCCCC)nc3)cn2)c(F)c1F
Yield: 39 %

Procedure:
The reaction of 2.5 mmol of 2-chloro-5-(6-hexyloxypyridin-3-yl)pyrimidine, 2.5 mmol of 2,3-difluoro-4-octylphenylboronic acid, 5 mmol of sodium carbonate and 0.025 mmol of tetrakis(triphenylphosphine)palladium(0) in 8 ml of toluene, 4 ml of ethanol and 4 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using dichloromethane/ethyl acetate 98:2 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.47 g (39%) of colorless crystals, X 94.5 SC 125.5 SA 156 I.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccncc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-bromo-1-pyridin-4-yl-ethanone hydrogen bromide (1.09 g) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.31 g), and the mixture was stirred at room temperature for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.20 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH2:5].Cl[C:19]([O:21][CH:22]1[CH:29]2[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2)=[O:20].C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH:5][C:19]([O:21][CH:22]1[CH:23]2[CH2:31][CH:27]3[CH2:26][CH:25]([CH2:30][CH:29]1[CH2:28]3)[CH2:24]2)=[O:20]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)[C@@](C)(N)Cc1ncc2ccccn12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@](C)(Cc1ncc2ccccn12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a stirred solution of the crude compound of Step 3 (0.83 g, 3.56 mmol) in dry THF (10 mL) was added a solution of 2-adamantyl chloroformate (0.80g, 3.7 mmol) in dry THF (3 mL) followed by a solution of triethylamine (0.38 g, 3.8 mmol) in dry THF (5 mL) dropwise. After 2 hours stirring, thereaction mixture was filtered, and the solvent removed in vacuo to give theproduct (1.2 g, 82%) as a colorless amorphous solid, which was used withoutfurther purification; IR (KBr) 1737 and 1699 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:18]=2[N:17]=1.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][O:31][C:33](=[O:35])[CH3:34])[C:18]=2[N:17]=1
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)CO)c2cc1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)COC(C)=O)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 68, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-2-methyl-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione (63 mg, 0.14 mmol) and acetyl chloride (18 ml, 0.25 mmol) in pyridine (1 ml) is heated at 50° C. for 18 hours. After evaporation, flash chromatography (19:1 dichloromethane-methanol elution) affords acetic acid 3-[8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-2-methyl-propyl ester, [MH]+ 482.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[NH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:22]O.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH2:21])=[O:22])[CH:18]=4)[NH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)OCCO4)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2[nH]nc(-c3ccc4c(c3)OCCO4)c2c1
Temperature: 45 °C
Yield: 50 %

Procedure:
A mixture of 3-(2H,3H-benzo[e]1,4-dioxin-6-yl)-1H-indazole-5-carbonitrile (0.230 g, 0.83 mmol), 95% ethanol, aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (80 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven and gave the title compound (0.098 g, 50% yield): 1H NMR (DMSO-d6) δ 13.31 (s, 1H), 8.55 (s, 1H), 8.17 (br s, 1H), 7.92 (d, 1H), 7.57 (d, 1H), 7.52 (m, 2H), 7.31 (br s, 1H), 7.02 (d, 1H), 4.32 (s, 4H); ES-MS (m/z) 296 [M+1]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[O:9][CH2:8][CH2:7][O:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][C:5]([O:6][CH2:7][CH3:8])=[O:9]
Reactant: O=C1OCCO1
Reactant: NCCO
Solvent: CCO
Product: CCOC(=O)NCCO
Reaction time: 2 h

Procedure:
40.6 grams of ethanolamine were charged to a standard neck reaction vessel fitted with an agitator, packed column and a thermometer. 70.3 grams of ethylene carbonate was added, and the temperature was allowed to rise to 100° C. The mixture was then held at 100° C. for 2 hours. The crude 2-hydroxyethyl urethane of ethanol formed had a viscosity of 4.5 poise at 30° C. (as measured by an ICI cone and plate viscometer) and a base number of 3.0. The residual base number corresponded to a conversion of amine to urethane of 99.4%. The mixture was heated to 150° C. and 689.1 grams of dodecanedioic acid were added. The solution was heated slowly to 220° C., with water being removed continuously, over a 1.5 hour period. The reaction product was then cooled and poured out. The final product had a melting point of 81° C. to 84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:5]=[C:6]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][OH:10])[CH:7]=1.[CH:25](=O)[CH3:26]>>[CH2:11]([C:8]1([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([S:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH:5]=2)[CH2:9][O:10][CH:25]([CH3:26])[O:13]1)[CH3:12]
Reactant: CC=O
Reactant: CCC(O)(CO)c1cc(F)cc(Sc2ccc3ccccc3c2)c1
Product: CCC1(c2cc(F)cc(Sc3ccc4ccccc4c3)c2)COC(C)O1
Yield: 86 %

Procedure:
Using a similar procedure to that described in Example 4, (+)-2-[5-fluoro-3-(naphth-2-ylthio)phenyl]butane-1,2-diol was reacted with acetaldehyde. There was thus obtained as a 2:1 mixture of diastereoisomers (+)-4-ethyl-4-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methyl-1,3-dioxolane in 86% yield as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[N:21]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:29][C:28]4[CH:27]=[CH:26][C:25]([C:22]5[N:23]=[N:24][N:20]([CH3:19])[N:21]=5)=[CH:32][CH:31]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cn1nnc(-c2ccc(C=O)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nnc(-c2ccc(CNc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)cc2)n1

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 282 mg (1.5 mmol) of 4-(2-methyl-2H-tetrazol-5-yl)-benzaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour and then reacted with two 440 mg (7 mmol) portions of NaCNBH3. 4-(3-Chloro-phenylamino)-3-[4-(2-methyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 232-235° C.; HPLC: tRet(grad20-100/20)=11.4; FAB-MS: (M+H)+=433.