Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([F:20])=[CH:13][C:14]=3F)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:21][O-:22].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([F:20])=[CH:13][C:14]=3[O:22][CH3:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2cccc(Br)n2)nc2cc(F)cc(F)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(F)cc2nc(-c3cccc(Br)n3)[nH]c(=O)c12
Reaction time: 24 h
Yield: 89 %

Procedure:
To a mixture of 2-(6-bromopyridin-2-yl)-5,7-difluoroquinazolin-4(3H)-one (12, 1.05 g, 3.11 mmol) and MeOH (15 mL) was added NaOMe (25% solution, 50 mL) at room temperature. After 24 hours, another portion of 25% NaOMe was added (25 mL). After an additional 48 hours at room temperature, the reaction was quenched with water and the pH adjusted to 7 with 2N HCl. The volume was reduced by half under reduced pressure and the remaining mixture was extracted with CH2Cl2 (3×250 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (970 mg, 89%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 10.56 (s, 1H), 8.57-8.43 (m, 1H), 7.79-7.74 (m, 1H), 7.71-7.62 (m, 1H), 7.09-6.99 (m, 1H), 6.71-6.65 (m, 1H), 4.02 (s, 3H).
Reaction SMILES: O[CH:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])[CH:3]=[CH2:4].CO[C:32]([O:37]C)([N:34]([CH3:36])[CH3:35])[CH3:33]>C1(C)C=CC=CC=1>[CH3:36][N:34]([CH3:35])[C:32](=[O:37])[CH2:33][CH2:4]/[CH:3]=[CH:2]/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: COC(C)(OC)N(C)C
Reactant: C=CC(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Solvent: Cc1ccccc1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/CCC(=O)N(C)C)ccc21
Yield: 76.6 %

Procedure:
A mixture of methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.8 g), N,N-dimethylacetamide dimethyl acetal (0.542 g, redistilled) in dry toluene (20 ml) was stirred and heated under reflux, under an atmosphere of nitrogen for 5 hr. The cooled solution was introduced directly onto a column of silica gel and the product purified by flash chromatography, eluting with ethyl acetate, to give methyl E-4-[5-[5-(dimethylamino)-5-oxopent-1-enyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.72 g, 77%) as an oil: partial NMR (250 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 2.45(m, 4H, CH2CH2CO), 2.82(s, 3H, NCH3), 2.98(s, 3H, NCH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.0(m, 4H, ArCH2Ar', NCH2), 6.2(d of t, 1H, CH2CH=CH), 6.45(d, J=15.8 Hz, 1H, CH2CH=CH).
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl.[Pd]>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: COC(=O)c1cc(O)ccn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(N)c3ccccc23)ccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
To a solution of 1-fluoro-4-nitro-naphthalene (1.0 g, 5.24 mmol) in dry DMF (22 mL) was added 4-hydroxy-pyridine-2-carboxylic acid methyl ester (0.993 g, 5.24 mmol) and K2CO3 (7.24 g, 52.4 mmol). The resulting yellow suspension was stirred at 100° C. under argon for five h. After cooling to room temperature, the solution was diluted with CH2Cl2 (62 mL) and 10% Pd/C (1 g) was added. The suspension was stirred under a H2 balloon for 72 h. The reaction was then filtered through a plug of diatomaceous earth and rinsed with EtOAc (150 mL) and extracted with H2O (3×100 mL), brine (1×100 mL) and dried over MgSO4. The solvent was removed via rotary evaporation and the resulting oil was applied to a flash silica column eluting with MeOH:CH2Cl2 (2:98) to provide the title compound (800 mg, 52%).
Reaction SMILES: Br[C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:16])[C:12]([F:15])([F:14])[F:13].BrC1C(OC)=CC=CC=1NC(=O)C(F)(F)F.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[F:13][C:12]([F:15])([F:14])[C:11]1[S:16][C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=2[N:10]=1
Reactant: COc1cccc(NC(=S)C(F)(F)F)c1Br
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COc1cccc(NC(=O)C(F)(F)F)c1Br
Solvent: C1COCCO1
Product: Oc1cccc2nc(C(F)(F)F)sc12
Temperature: 25 °C

Procedure:
Synthesis of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroethanethioamide (C25). A solution of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroacetamide (C24) (776 mg, 2.6 mmol) and Lawesson's reagent (1.07 g, 2.6 mmol) in 1,4-dioxane (13 mL) was heated to 135° C. overnight. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. Purification via silica get chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as an oil. Yield: 839 mg, 2.60 mmol, quantitative. LCMS m/z 314.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 6.92 (dd, J=8.3, 1.1 Hz, 1H), 7.39 (dd, J=8.4, 8.3 Hz, 1H), 8.28 (dd, J=8.2, 0.8 Hz, 1H), 9.75 (br s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[CH2:40][CH2:39][O:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[CH2:40][CH2:39][O:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
TFA (3.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (720.2 mg, 1.070 mmol) in DCM (3.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to give the title compound as a white solid (187.7 mg, 37%). LCMS calc. for C22H23F2N6O2S (M+H)+: m/z=473.1. found 473.2. 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.68-7.39 (m, 3H), 7.26 (t, J=8.8 Hz, 2H), 4.48 (t, J=8.9 Hz, 2H), 3.37 (t, J=8.5 Hz, 2H), 3.14-3.01 (m, 1H), 3.00-2.90 (m, 1H), 2.89-2.81 (m, 1H), 2.77-2.69 (m, 1H), 2.55-2.50 (m, 1H), 1.83-1.59 (m, 3H), 1.12-1.00 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C:13]([O:15][C@:10]3([CH3:16])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:18])([CH3:17])[CH2:5][CH2:4][CH2:3]2)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH:20]=1.CC1N(CCCO)C2C=CN=CC=2N=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][O:28][CH:12]2[CH2:13][O:15][C:10]3([CH3:16])[CH2:9][CH2:8][CH:7]4[C:2]([CH3:1])([CH:11]23)[CH2:3][CH2:4][CH2:5][C:6]4([CH3:18])[CH3:17])[CH:20]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CC(=O)O[C@]3(C)CC[C@@H]12
Reactant: OCCCc1cccnc1
Agent: Cc1nc2cnccc2n1CCCO
Product: CC1(C)CCCC2(C)C1CCC1(C)OCC(OCCCc3cccnc3)C12
Yield: 75 %

Procedure:
2-(3-(3-Pyridyl)propoxy-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan was prepared by the procedure of Example 2 employing (3aR)-(+)-sclareolide in lieu of undecanoic-gamma-lactone and 3-(3-pyridyl)propanol in lieu of 3-(2-methylimidazo [4,5 -c]pyrid-1-yl)propanol.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].CS[C:10]1[S:11][CH2:12][CH2:13][N:14]=1>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[C:10]1[NH:14][CH2:13][CH2:12][S:11]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)NN
Reactant: CSC1=NCCS1
Solvent: CCO
Product: CCOC(=O)NN=C1NCCS1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A mixture of ethyl carbazate (23.4 g), 2-(methylthio)-2-thiazoline (25 g) and ethanol (250 ml) was heated to reflux for 3 days. It was then stirred at room temperature for 2 days. The precipitate was collected by filtration and washed with ethanol to obtain the title compound (9.05 g).
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:6])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=729 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH3:20])[O:25][N:24]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: Cc1cc(C(=O)O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)no1
Yield: 40.8 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 5-methylisoxazole-3-carboxylic acid (0.120 g, 0.946 mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol) and EDCI (0.181 g, 0.946 mmol) using DCM as solvent using the method of Example 34(d) affording 0.114 g of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (m, 3H), 2.48 (d, 3H), 2.56 (m, 3H), 4.29 (m, 1H), 4.43 (m, 1H), 4.59 (m, 1H), 6.41 (m, 1H), 6.44 (d, 1H), 7.44 (m, 1H), 7.50 (d, 1H), 7.56 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([CH2:16][C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:13]([CH2:24]O)=[CH:12][N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].O>C1(C)C=CC=CC=1>[Br:46][CH2:24][C:13]1[CH:14]=[C:15]([CH2:16][C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC2(C#N)CCCC2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ncc(CBr)cc2CC2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a solution of 1-((2-(2-fluoro-5-methoxyphenyl)-5-(hydroxymethyl)pyridin-3-yl)methyl)cyclopentanecarbonitrile (353 mg) and triphenylphosphine (410 mg) in toluene (10 mL) was added carbon tetrabromide (512 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (339 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(O)c(F)c1
Yield: 90.3 %

Procedure:
2,6-Difluoro-4-nitrophenol (1.75 g, 10 mmol) and 10% palladium on carbon catalyst (0.3 g) in ethanol (100 ml) were shaken in a closed vessel under an initial hydrogen pressure of 3.5 bar. When hydrogen uptake was complete, the catalyst was filtered off, and the filtrate evaporated to a solid, triturated with petroleum ether, filtered, washed and dried to give the title compound (1.31 g), m.p. indeterminate.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:10].NC(N)=O>[N+]([O-])(O)=O>[Cl:10][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: Cl
Agent: NC(N)=O
Solvent: O=[N+]([O-])O
Product: CC(C)C[C@H](Cl)C(=O)O
Temperature: 80 °C

Procedure:
L-(+)-Leucine (10 g, 0.076 moles) is mixed with 24 mL of concentrated HCl and 10 mL of concentrated HNO3 with the addition of 2 g of urea and subsequently heated for 1 hour at 80° C. and then for 1 hour at 50° C. on a water bath (complete dissolution of the acid with heavy foaming). After cooling, the solution is extracted with ether several times, the ether extract is washed with water and dried over calcium chloride, the solvent is distilled off in a rotary evaporator and the residue is fractionally distilled under vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:28])[C:17]2[CH:27]=[CH:26][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:32](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:17]2[CH:27]=[CH:26][C:20]3[CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:19]=3[CH:18]=2)=[O:28])[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCNCC2
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN1CCc2ccc(C(=O)Cn3ccc(OCc4ccccc4)cc3=O)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.00 g (5.15 mmol) 4-benzyloxy-1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-ethyl]-1H-pyridin-2-one (preparation 22.3) in 20 mL THF is added 0.41 mL (5.51 mmol) aqueous 37% formaldehyde solution. The mixture is acidified (pH 4-5) with acetic acid and then 1.27 g (5.97 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred overnight at RT, diluted with aqueous saturated NaHCO3-solution until pH 7 and THF is evaporated. The residue is diluted with EtOAc, the layers are separated and the organic phase is concentrated. The residue is elutriated in tert-butylmethylether and is collected by filtration. The residue is dissolved in DMF and purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.C(O)(=O)C.Cl>C(OCC)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[O:6][C:5]([CH3:7])=[C:2]([CH3:1])[N+:3]=2[O-:4])=[CH:11][CH:10]=1
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C

Procedure:
1.00 g (9.89 mmol) of diacetyl monoxime and 1.53 g (10.88 mmol) of 4-chlorobenzaldehyde were initially charged in 2 ml (34.94 mmol) of glacial acetic acid. Then, while the reaction mixture was cooled with ice, hydrogen chloride gas was introduced for 30 min. 10 ml of diethyl ether were then added to the reaction mixture. A precipitate was formed which was filtered off and washed twice with in each case 2 ml of diethyl ether. The precipitate was resuspended in about 5 ml of water and the suspension was made basic using 25% strength aqueous ammonia solution. The mixture was extracted four times with in each case 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Without further purification, the residue was used for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[OH:20]O>ClCCl.C[Re](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:14]2[CH:15]=[CH:16][N+:17]([O-:20])=[CH:18][CH:19]=2)([O:10][CH3:11])[O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: OO
Reactant: COC(Cc1ccc(F)cc1)(OC)c1ccncc1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: COC(Cc1ccc(F)cc1)(OC)c1cc[n+]([O-])cc1
Temperature: 25 °C

Procedure:
55 g (0.21 mole) of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine and 445 mg of methyltrioxorhenium are dissolved in 250 mL of dichloromethane. 112 mL of commercial hydrogen peroxide solution is added to the reaction mixture which is further stirred over night at room temperature. The reaction mixture is then decanted and the organic phase is washed with sodium hydrogen sulfate and water and dried over magnesium sulfate. After concentration, 33 g of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine 1-oxide is obtained as a green oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5](C(O[Si](C)(C)C)(C#N)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl.O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:20]([C:19]([OH:22])=[O:21])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1(C#N)CCOc2cc(F)ccc21
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1CCOc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
7-Fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile (750 mg, 2.83 mmol) and SnCl2 dihydrate (2551 mg, 11.3 mmol) were diluted with glacial acetic acid (3 mL) and concentrated HCl (3 mL). The reaction was heated in an oil bath at 130° C. and stirred overnight. The reaction was allowed to cool, diluted with water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (465 mg, 83.9% yield).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 8 h
Yield: 75 %

Procedure:
N-benzyl-4-nitrobenzenesulfonamid (60 g, 1 eq) was dissolved in anhydrous ethanol (2 l) and Pd/C (10 g, 1 eq) was added under inert atmosphere. The mixture was stirred under a hydrogen atmosphere for 8 h. Then the solution was filtered over Celite, concentrated in vacuo to ˜40 ml and then crystallized. The product was washed twice with ethanol (20 ml) at 4° C., filtered and dried in vacuo to give 4-amino-N-benzylbenzenesulfonamide. Yield 75%.
Reaction SMILES: [NH2:1][C@:2]([CH3:14])([CH2:5][CH2:6][C:7]1[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:15](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:16].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:14][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:15](=[O:16])[NH:1]1
Reactant: CCn1cccc1CC[C@@](C)(N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCn1cccc1CC[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
The thus obtained (2R)-2-amino-2-methyl-4-(1-ethylpyrrol-2-yl)butan-1-ol ½ D-(−)-tartrate (55.5 mg, 0.160 mmol) was suspended in methylene chloride (1.6 mL) and di-t-butyl dicarbonate (0.17 g, 0.78 mmol), triethylamine (0.22 mL, 1.58 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) were added thereto, followed by stirring of the mixture at room temperature for 20 minutes. Water and ethyl acetate were added thereto to separate it. The thus obtained organic phase was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 1:1) to obtain (4R)-4-methyl-4-[2-(1-ethylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (18.0 mg, yield: 58%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([CH3:3])[CH3:2].[Br:13]Br>>[Br:13][CH2:11][C:10]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cnccc1C(C)C
Product: CC(C)c1ccncc1C(=O)CBr

Procedure:
By the reaction in the same manner as in Example 53-ii) using 1-(4-isopropylpyridin-3-yl)ethanone (0.90 g) and bromine (0.63 g), crude 2-bromo-1-(4-isopropylpyridin-3-yl)ethanone hydrobromate (1.70 g) was obtained as a pale-brown amorphous compound. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-isopropylpyridin-3-yl)ethanone hydrobromate (340 mg) and 3-(aminocarbonothionyl)benzamide (240 mg), the title compound (59 mg) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCC(C)C)ncnc32)[C@]1(C)F
Yield: 41.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added isobutyl amine (about 1.03 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.18 g) as a colorless gummy mass. Yield: 41.6%; 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-7.79 (m, 3H), 7.58-7.55 (m, 3H), 6.54 (d, 1H, J=23.4 Hz), 5.90 (bs, 1H), 4.83-4.78 (m, 2H), 4.49-4.44 (m, 1H), 3.49 (m, 2H), 2.14 (s, 3H), 2.09-1.90 (m, 1H), 1.89 (d, 3H, J=2.4 Hz), 1.45 (d, 3H, J=22.8 Hz), 1.02 (d, 6H, J=6.6 Hz); Mass: [M+1]+ 500 (100%), 501 (35%); IR cm−: 3372, 3141, 2927, 1752, 1622, 1274, 1063, 1026, 952, 713; HPLC: 94.7%.