Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[O:22][CH:23]=1>CC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[O:22][CH:23]=[C:19]([CH2:18][N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[CH3:12])[N:20]=2)=[CH:25][CH:26]=1
Reactant: CC1CCCN1Cc1coc(-c2ccc(O)cc2)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1CCCN1Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-3-chloropropane (0.7 mmol, 2 eq, 11.5 mg), potassium carbonate (0.7 mmol, 2 eq, 98 mg) and 4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl}phenol ax65 (0.35 mmol, 1 eq, 91.5 mg) in acetone (1.25 ml) is stirred at 56° C. overnight. The mixture is then filtered, washed with acetone (2×500 μl), and the solvent is removed under reduced pressure. The residue is dissolved in 3.5 ml of dichloromethane and washed twice with water (2×3.5 ml) and finally with brine (3.5 ml). The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude product is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1CCCCl
Yield: 40.3 %

Procedure:
Crude 6-Chloro-7-nitro-4H-benzo[1,4]oxazin-3-one (81MF2253a) (2.60 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2253b) (1.23 g, 36%). 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.20 (s, 1H), 4.70 (s, 2H), 4.12 (t, J=7.6 Hz, 2H), 3.67-3.59 (m, 2H), 2.21-2.13 (m, 2H); 13C NMR (CDCl3) δ 163.6, 143.5, 133.3, 133.2, 122.4, 117.2, 115.2, 67.4, 42.1, 39.6, 29.8.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: NC(=O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: NC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.5 g) in 2-propanol (15 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (0.65 g) and piperidinium acetate (0.64 g). The reaction mixture was stirred at 80° C. for 3 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/heptane/ethanol/water to give the title compound (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(CO)ccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (3.1 g, 11.18 mmol) in CH2Cl2 (30 mL) was added MnO2 (4.85 g, 55.9 mmol). The resulting mixture was stirred at RT under N2 gas for 18 h. Solvent was separated from MnO2 by passing through the Celite®. Solvent was evaporated in vacuo to give the final product. MS m/z: 276.5 (M+H). Calc'd. for C16H21NO3-275.34.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([O:18][CH3:19])[C:16]=3[N:17]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27].[F-].[K+].[H+].[B-](F)(F)(F)F>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]=[CH:13][N:14]=[C:15]([O:18][CH3:19])[C:16]=4[N:17]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1ncnc2ccc(-c3cccnc3Cl)nc12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: [F-]
Agent: [H+]
Solvent: C1COCCO1
Product: COc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (2.0 g, 7.3 mmol), 3-chloro-4-fluoro-phenylboronic acid (2.5 g, 14.3 mmol), KF (2.5 g, 43.0 mmol) and 1,4-dioxane (75 mL) and stir bar were added to a reaction flask. The contents were degassed by vacuum and back filled with argon three times while stirring. Subsequently, commercially available catalyst Pd2(dba)3.t-Bu3P.HBF4 (1:2) (1 g, 0.67 mmol) was added to the reaction contents, repeated degassing cycles and heated at 90° C. under argon. Colorimetric changes were observed after the introduction of catalyst and as the reaction progressed from pale pink to yellow to off-green slurries. After 6 h, the reaction stirring was stopped, filtered the hot slurry and washed the cake with additional amount of dioxane (30 mL). The pale yellow clear filtrate solution was passed through a pad of Celite® and concentrated the filtrate. The crude solid residue was partitioned between CH2Cl2 (150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in 60% EtOAc/hexanes (30 mL), suction filtered and dried the solid to obtain 1.6 g of (purity: 95%) 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine as an off-white solid. The filtrate was concentrated and purified the concentrate by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexanes eluting solvent gradient) to obtain additional 0.65 of titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:6]=2[CH:18]=1.[Li+].[OH-].O.Cl>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
Ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (52.6 g, 0.173 mol) and LiOH (8.31 g, 0.347 mol) were combined in 750 mL of THF and 150 mL of water and stirred at room temperature for 18 hours, after which time HPLC indicated loss of the starting material. 80 mL of concentrated HCl was added and the mixture was stirred for 1 hour, and then evaporated to dryness. The residue was dissolved in EtOAc and water was added. The layers were separated and the organic layer was washed with water (2×). The organic layer was dried over magnesium sulphate and concentrated to give 45.5 g (0.165 mol, 95%) of 6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid. MS (ES) m/e 278 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[O:3].O.[O-:25][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:25])=[O:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)(=O)=O
Yield: 81.5 %

Procedure:
The sulfoxide of Example 37, (100 mg, 0.3 mmoles) was stirred in 4 mL of CH2Cl2 and 8 mL water with 20 mg (0.09 mmole) of benzyltriethylammonium chloride and 94.5 mg (0.6 mmole) KMnO4 at 25° C. for 16 h. The mixture was partitioned between 60 mL EtOAc and 40 mL water and the EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 25% EtOAc/hexanes to give 85 mg product (81% yield); mp 174-175.3° C. Elemental analysis for C18H25N3O2S: Theory C, 62.22; H, 7.25; N, 12.09; S, 9.23. Found: C, 62.13; H, 7.28; N, 11.93; S, 9.12.
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[C:42]([O-])([O-])=O.[Cs+].[Cs+]>CO>[Si:30]([O:29][C@@H:28]1[C@@H:27]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([O:10][CH3:42])[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and methanol (1.0 mL). The reaction mixture was flushed with N2 and stirred at room temperature for 1 h after which the mixture was evaporated to dryness. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 38 mg (77% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.12. 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H, Ar—H), 8.27 (s, 1H, Ar—H), 6.49 (t, 1H, H-1′, J=6.3), 4.62 (m, 1H, H-3′), 4.18 (s, 3H, OCH3), 4.01 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.77 (dd, 1H, H-5′, J=11.2, 2.9), 2.62 (app quint, 1H, H-2′, Japp˜6.3), 2.45 (ddd, 1H, H-2′, J=13.2, 6.4, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 161.1, 152.0, 151.5, 140.6, 122.0, 88.0, 84.5, 71.9, 62.8, 54.0, 41.4, 25.9, 25.7, 18.4, 17.9, −4.7, −4.8, −5.5, −5.6. FAB HRMS calcd for C23H43N4O4Si2 (M++H) 495.2823. found 495.2798.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:9][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7]1)=[O:5].[CH3:31][C:32]1[N:36]=[CH:35][NH:34][C:33]=1[CH2:37][CH2:38][C:39](Cl)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.O>[CH2:18]([O:17][C:8]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:39](=[O:40])[CH2:38][CH2:37][C:33]2[NH:34][CH:35]=[N:36][C:32]=2[CH3:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:9]1)[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc[nH]c1CCC(=O)Cl
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2[nH]cnc2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
146 mg (0.34 mmol) of (R)-2-amino-3-(4-methoxy-phenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-one hydrochloride in solution in 2 ml of dimethylformamide are added to a solution of 64 mg (0.34 mmol) of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride, 119 mg (2.34 mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 154 mg of N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 86%.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=1)[C:33]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:34])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cccc(CC(NC(=O)OC(C)(C)C)C(=O)O)c1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(CC(NC(=O)OC(C)(C)C)C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (400 mg, 1.15 mmol), 2-tert-butoxycarbonylamino-3-m-tolyl-propionic acid (334 mg, 1.2 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 50 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 218 mg, 1.15 mmol), and DMF (5 mL) was shaken at room temperature for 8 hours. The reaction mixture was poured into 20 mL of ethyl acetate, washed with 5 mL of 2N HCl solution, saturated NaHCO3 (20 mL), water (10 mL), and brine (10 mL). The organic layer was concentrated under vacuum and purified by column (silica gel, EtOAc/hexane 1/1) to afford the intermediate [2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]piperidin-1-yl}-1-(3-methylbenzyl)-2-oxo-ethyl]carbamic acid tert-butyl ester as colorless oil (600 mg, yield 85%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Yield: 100 %

Procedure:
A mixture of 56 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-4-(phenylmethyl)piperazine and 480 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 46.9 parts (100%) of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine as a residue (int. 16).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([CH:16]([CH3:18])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Agent: [Pd]
Product: CCCCOc1nccc2nc(C(C)C)c3ccc(F)cc3c12
Reaction time: 6 h

Procedure:
1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (50 mg, 0.161 mmol) and 5% Pd on Carbon; Type A470129-5® (Johnson Matthey) (5 mg, 0.161 mmol) were combined in a vial. The vial was flushed with nitrogen for several minutes, and then EtOH (1.0 ml) was added. The reaction mixture was stirred under hydrogen (balloon pressure) for 6 hr. The reaction mixture was flushed with nitrogen, diluted with EtOAc (5 mL), and then filtered through a syringe filter to remove Pd/C. The filtrate was concentrated, and the resulting residue was adsorbed on to silica gel, then purified by column chromatography on silica gel eluting with an EtOAc/hexanes gradient to afford 1-butoxy-9-fluoro-6-isopropylbenzo[c]-1,6-naphthyridine. LRMS (ESI) calc'd for (C19H21FN2O) [M+H]+, 313.2; found 313.1.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3][S:2]1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15].P(C#N)(OCC)(OCC)=O>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[S:1]1[CH2:5][CH:4]([C:6]([NH:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:16])=[O:8])[CH2:3][S:2]1
Reactant: O=C(O)C1CSSC1
Reactant: COC(=O)CCN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)C1CSSC1
Yield: 9.4 %

Procedure:
The reaction was carried out as described in Example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine, 502 mg of β-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2:1 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([CH3:10])[CH:8]=[O:9].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([CH3:10])[CH2:8][OH:9]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (2.0 g, 6.68 mmol) in ethanol (30 mL) is added to NaBH4 (0.25 g, 6.6 mmol) in portions at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using water, extracted with ethyl acetate, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate yields the title compound (2.0 g).
Reaction SMILES: ClOC(C)(C)C.[F:7][C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19].C(N(CC)CC)C>C(OCC)(=O)C>[F:7][C:8]1[CH:18]=[CH:17][C:11]2[N:12]=[C:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19]
Reactant: C[C@@H]1COc2c(ccc(F)c2F)N1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=Nc2ccc(F)c(F)c2OC1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
In a nitrogen stream, a solution of 2.11 ml of t-butyl hypochlorite and 2 ml of ethyl acetate were added dropwise to a mixture of 1.54 g of (R)-(+)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine (optical purity: 71.7% e.e., (R)), 5.21 ml of triethylamine and 9 ml of ethyl acetate while keeping the internal temperature at -52° C. over a period of about 4 minutes, and the resulting mixture was further stirred at -60° to -50° C. for 30 minutes. The reaction mixture was washed twice with 10 ml portions of 5% aqueous solution of citric acid and further with 10 ml of dilute aqueous ammonia (concentrated aqueous ammonia:water=1:4 (v/v)) and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the oily residue was purified over silica gel (50 g) column chromatography using chloroform (the bottom layer after shaking with concentrated aqueous ammonia) as the eluent. The solvent was removed from the eluate under reduced pressure to yield 693 mg of 7,8-difluoro-3-methyl-2H-[1,4]benzoxazine as pale yellow crystals (yield: 60.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid ethyl ester (1.89 g, 10.0 mmol) and benzylbromide (1.71 g, 10.0 mmol) in acetone (50 mL) was added cesium carbonate (3.26 g, 10.0 mmol). The mixture was heated to reflux overnight and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 1-benzyl-1H-indole-2-carboxylic acid ethyl ester (2.38 g, 85%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 7.68 (d, 1H), 7.37-7.11 (m, 7H), 7.02 (d, 2H), 5.82 (s, 2H), 4.30 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.IC1C=CC=C([F:27])C=1>>[F:27][C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc(I)c1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Product: COc1cc(C#Cc2cccc(F)c2)cnc1OC

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-3-fluorobenzene instead of 1-iodo-2-methylbenzene.