Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:35][OH:36]>>[C:16]([O:15][C@@H:9]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([O:36][CH3:35])[O:7][C@H:8]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:20]=1)(=[O:18])[CH3:17]
Reactant: CO
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)OC(Br)[C@H]1OC(C)=O
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (3S,4R,5S,6S)-2-bromo-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.02 g, 3.62 mmol) in methanol (15 mL) was added ZnO (294.5 mg, 3.62 mmol) at 60° C. The reaction mixture was stirred at 60° C. for 1 h. After completion of reaction, as confirmed by TLC, reaction mixture was passed through sintered funnel to remove the solids. The filterate was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:Pet. Ether) to afford title compound (1.1 g, 65%)
Reaction SMILES: Cl.[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH:33]=O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C([BH3-])#N.[Na+].CO>CC(O)=O>[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:33][CH2:32][C:30]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:23][CH3:22])[CH:31]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(C(F)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CCN2CCN(CC(F)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Reaction time: 12 h

Procedure:
5-(1-Fluoro-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one hydrochloride (30 mg, 0.11 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (37 mg, 0.22 mmol), sodium cyanoborohydride (67 mg, 1.078 mmol) were added to a 25 mL flask containing a stir bar; to the flask was added MeOH (3 mL) and few drops of AcOH. The reaction mixture was subsequently stirred for 12 hr; LC indicated that reaction had gone to completion. The solution was concentrated to dryness, redissolved in EtOAc (15 mL) and washed with aq. NaHCO3 and aq. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then re-dissolved in MeOH (3.5 mL) again, filtered and shot into mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Reaction time: 64 h
Yield: 88.8 %

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.6 g) in ethanol/THF (10/10 ml) was added at room temperature 1N sodium hydroxide solution (2 ml), and the mixture was stirred for 64 hours. To the mixture was added 1N hydrochloric acid (3 ml), and the mixture was concentrated. The resulting solid was collected by filtration, which was washed with water, 2-propanol and diisopropylether to give pale yellow powder of 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic acid (510.6 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[OH-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CS(C)=O.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][O:9][CH2:17][CH:19]1[O:21][CH2:20]1)=[NH:7]
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N=C(NOCC1CO1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
50 g (0.245 mol) of m-trifluoromethyl-benzamidoxime and 33.7 g (0.6 mol) of potassium hydroxide was dissolved in a mixture of dimethyl sulphoxide and 170 ml of water, and the mixture was cooled to 0° C. 48 ml (0.6 mol) of epichlorohydrine was added, and the reaction mixture was stirred at 0° C. for 5 hours, then kept in a refrigerator overnight. Next day 250 ml of water was added, and the mixture was extracted with ethyl acetate (4×250 ml). The combined organic phases were washed with water, dried, treated with charcoal and evaporated to dryness, to yield m-trifluoromethyl-N-(2,3-epoxypropoxy)-benzamidine, as a colorless oil.
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5](=[O:28])/[C:6](/[O:25][CH2:26][CH3:27])=[CH:7]/[C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)C.[H][H].Cl>CO.C1COCC1>[CH3:2][O:4][C:5](=[O:28])[CH:6]([O:25][CH2:26][CH3:27])[CH2:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[C:11]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c2ccoc12)OCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(Cc1ccc(OCc2ccccc2)c2ccoc12)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
Magnesium turnings (0.5 g, 20.6 mmol) were added to a stirred solution of 3-(4-benzyloxy-benzofuran-7-yl)-2Z-ethoxy-acrylic acid ethyl ester (0.8 g, 2.18 mmol) in methanol (26 ml) and THF (13 ml) at ambient temperature. The suspension was warmed to 40° C. until evolution of hydrogen commenced. Then, the heating bath was replaced by a water bath, additional magnesium turnings (1 g, 41.2 mmol) were added and stirring of the reaction mixture was continued for 12 h. The suspension was cooled to 0° C., then 25% aqueous hydrochloric acid was added till all the solid had dissolved. The mixture was extracted twice with ethyl acetate and the combined ethyl acetate solutions were washed three times with water and dried over sodium sulfate. The solvent was evaporated to afford the title compound (0.77 g, 2.16 mmol, 99%) which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[N:8][CH:7]=[CH:6]2.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[N:8][CH:7]=[CH:6]2
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc2c(O)nccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(OCCN3CCCCC3)nccc2c1
Yield: 92 %

Procedure:
To a solution of 6-methoxyisoquinoline-1-ol (1.00 g, 5.71 mmol) in acetone, K2CO3 (4.73 g, 34.26 mmol) and N-chloroethyl-piperidine hydrochloride salt (1.37 g, 7.42 mmol) were added. The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by adding water, then extracted with ethyl acetate. The organic layers were separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica-gel; methylene chloride/methanol=9/1 v/v) to give a yellow oil product, 1.50 g, 92.0% yield. MS: 287.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (d, 1H, J=9.0 Hz), 7.39 (d, 1H, J=7.5 Hz), 7.10-7.13 (m, 2H), 6.51 (d, 1H, J=7.5 Hz), 4.02 (t, 2H, J=6.6 Hz), 3.86 (s, 3H), 2.55 (t, 2H, J=6.5 Hz), 2.41 (br, 4H), 1.52-1.44 (m, 4H), 1.37-114 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[CH3:9].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)cc1Br
Temperature: 0 °C
Yield: 48.3 %

Procedure:
25 g (134 mmol) of 2-bromo-4-aminotoluene are placed in 400 ml of 1M sulfuric acid in a round-bottomed flask, and the mixture is then cooled to 0° C. 13 g (190 mmol) of sodium nitrite dissolved in 30 ml of water are added, followed by addition of 21 ml of concentrated sulfuric acid. The mixture is refluxed for 4 hours. It is then extracted with ethyl ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10) to give 12.1 g (48%) of the expected product in the form of a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:15](=[O:17])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]1=2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NCc2ccccc2)CCN(C)C1
Reaction time: 16 h

Procedure:
2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (CD58) was mixed with EDCI and benzylamine and the reaction mixture was stirred for 16 h to obtain N-benzyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.CC1C=CC(S([CH2:35][N+:36]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+].CC(O)(C)C>COCCOC.O>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:35]#[N:36])[CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To a solution of bis(3-(trifluoromethoxy)phenyl)methanone (9.94 g, 28.4 mmol), prepared as described in Procedure 13, in DME (200 mL) was added TosMIC (7.49 g, 38.3 mmol). The reaction mixture was cooled in an ice-bath and a 1.0 M solution of t-BuOK in t-BuOH (77 mL, 77 mmol) in DME (77 mL) was added via cannula as a slow stream. Upon completion of addition, the ice-bath was removed and the reaction mixture was stirred at rt for 16 h. After this time, additional TosMIC (3.75 g, 19.2 mmol) was added at rt and the reaction mixture was stirred for an additional hour. At the conclusion of this period, the reaction was poured into H2O (150 mL) and extracted with hexane (3×200 mL). The organic portions were combined and dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 0 to 15% EtOAc/hexane to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (6.7 g, 67% yield) as a clear yellow oil. LCMS: RT=3.90 min [M−H] 360.2 (2 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 5.18 (s, 1 H), 7.18 (s, 2 H), 7.24 (d, J=9.67 Hz, 2 H), 7.30 (d, J=7.91 Hz, 2 H), 7.46 (t, J=7.91 Hz, 2 H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([OH:14])[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:13][CH:10]1[CH2:11][CH2:12][CH:7]([OH:14])[CH2:8][CH2:9]1
Reactant: OC1CCC(O)CC1
Reactant: C1=COCCC1
Solvent: Cc1ccccc1
Product: OC1CCC(OC2CCCCO2)CC1
Reaction time: 17 h
Yield: 0.1 %

Procedure:
An acidic resin (Dowex 50W×8, trade name, Dow Chemical Company, 800 mg) and dihydropyran (1.89 ml, 20.7 mol) were added dropwise to a solution of 1,4-cyclohexanediol (4.0 g, 34.4 mol) in toluene (80 ml) at room temperature and vigorously stirred. After 17 hours, the reaction mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-(tetrahydro-2H-pyran-2-yloxy)cyclo-hexanol (2.69 g, 65%).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:15]=1[CH2:16][N:17]1[C:25](=[O:26])[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]2[C:18]1=[N:19][C:20]([NH:34][C:35]1[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=1[NH2:43])=[N:21][CH:22]=2.C(OC)(OC)OC>CO>[F:13][C:14]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:15]=1[CH2:16][N:17]1[C:25](=[O:26])[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]2[C:18]1=[N:19][C:20]([N:34]1[C:35]3[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=3[N:43]=[CH:2]1)=[N:21][CH:22]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(Nc3cc(C#N)ccc3N)ncc21
Solvent: O
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(-n3cnc4ccc(C#N)cc43)ncc21

Procedure:
A catalytic amount of para-toluene sulfonic acid monohydrate was added to a solution of the above amine intermediate and trimethyl orthoformate (3 mL) in MeOH (10 mL). After 1 hr the crude material was adsorbed onto silica gel and purified by column chromatography (eluted with 1 and 2% MeOH/DCM) to yield tert-Butyl 9-(2,6-difluorobenzyl)-2-(6-cyano-1H-benzo[d]imidazol-1-yl)-8-oxo-8,9-dihydropurine-7-carboxylate (60) (164 mg), MH+=504 and MH+-BOC=404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:49])([F:48])[C@:29]([C:32]3[CH:37]=[C:36](B4OCC(C)(C)CO4)[C:35]([F:46])=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[C:51]1[O:52][C:53]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:54]=2[N:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCCC1.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:48])([F:49])[C@:29]([C:32]3[CH:37]=[C:36]([C:51]4[O:52][C:53]5[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:54]=5[N:55]=4)[C:35]([F:46])=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)c(F)cc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)c(F)cc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 50.4 %

Procedure:
In a tube a mixture of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (intermediate D1.1) (130 mg, 144 μmol), 2,6-dichlorobenzo[d]oxazole (30.4 mg, 159 μmol), and cesium carbonate (188 mg, 576 μmol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for 5 minutes. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.88 mg, 7.21 μmol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours. After evaporation, the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (52 mg, 50% yield) was obtained as a pale yellow solid. MS (ISP): m/z=716.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2OC)nc1Cl
Yield: 87 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (102e) (90 mg, 0.21 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (3 mL), to obtain 74 mg of the title compound as a light pink solid (85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH2:16](Br)[CH:17]=[CH2:18].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:18]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2]=2[NH2:1])[CH2:7]1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Nc1c2c(cc3ccccc13)CNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCN1CCc2c(cc3ccccc3c2N)C1
Temperature: 25 °C

Procedure:
A mixture of 7.9 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline, 5.3 g of allyl bromide, 2.6 g of triethylamine in 50 ml of anhydrous chloroform is heated to the boil for 4.5 hours while stirring. 100 ml of water are added to the resulting solution after cooling to room temperature, the solution is made alkaline with 40% caustic soda solution, and the organic phase is separated off. The organic solution is washed neutral with water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallized twice from methanol. M.Pt. of the title compound: 74° - 76°.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([N:7]([CH3:8])[CH3:6])=[O:43])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
TSTU (108 mg, 0.36 mmol) was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (115 mg, 0.36 mmol, as described in Example 3.00) and DIPEA (0.069 mL, 0.40 mmol) suspended in DCM (1 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. Dimethylamine (0.180 ml, 0.36 mmol) was then added and stirring was maintained for an additional 30 min. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to afford 8-(1-hydroxyethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (123 mg, 0.355 mmol, 99%) as a off-white solid. Mass Spectrum: M+H+ 347.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:19])[S:9](=[O:18])(=[O:17])[N:10]([CH2:11][CH:12]3[CH2:14][C:13]3([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[C:26]([F:34])=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:13]1([F:16])[CH2:14][CH:12]1[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:27]3[C:26]([F:34])=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:3][CH:4]=2)[N:8]([CH3:19])[S:9]1(=[O:18])=[O:17]
Reactant: CN1c2nc(Cl)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: CCOC(=O)c1cccc(B(O)O)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccc3c(n2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1F
Temperature: 75 °C

Procedure:
5-chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (29-1) (2.2 g, 7.1 mmol, 1.0 eq), [3-(ethoxycarbonyl)-2-fluorophenyl]boronic acid (3.0 g, 14 mmol, 2.0 eq), tripotassium phosphate (3.0 g, 14.2 mmol, 2.0 eq), S-Phos (0.29 g, 0.71 mmol, 0.1 eq), and palladium(II) acetate (0.080 mg, 0.36 mmol, 0.05 eq) were combined in THF (15 mL) and water (2 mL). The resulting mixture was heated at 75° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (100 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-60% EtOAc in hexanes) to afford ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate (37-1) as a yellow solid. LRMS m/z (M+H) 442.2 found, 442.1 required.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[NH:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:18]2[CH2:19][CH2:20][NH:21][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][O:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:17]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1cc(N2CCOCC2)ccc1[C@@H]1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCOCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of the above prepared (3R)-3-(4-(morpholin-4-yl)phenyl)piperazine trihydrochloride (0.5 g, 1.40 mmol) and triethylamine (0.8 g, 7.91 mmol) in tetrahydrofuran (10 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-(3H)-pyrimidin-4-one (0.3 g, 1.25 mmol) which was prepared by Reference Example 2 portionwise. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-morpholin-4-yl-phenyl)-piperazin-l-yl)-3H-pyrimidin-4-one (0.41 g, 0.91 mmol, 73%) as white crystals.