Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29](O)=[O:30])[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][C:64]=1[O:71][CH3:72]>>[C:67]([C:66]1[CH:69]=[CH:70][C:63]([NH:62][C:29]([CH:20]2[NH:19][CH:18]([CH2:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:30])=[C:64]([O:71][CH3:72])[CH:65]=1)#[N:68]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (1.0 g, 1.8 mmol), was reacted with diisopropylethylamine (2.1 g, 16.5 mmol), diphenylphosphinic chloride (1.74 g, 7.3 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.54 g, 3.7 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield, 0.17 g, 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])([O-])=O.[NH4+].[Cl-]>[Fe].CCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:20])([F:21])[F:22])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N)c1

Procedure:
A mixture of N-(3-nitro-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (3.4 g, 11 mmol), Fe (3.7 g, 66 mmol), saturated aqueous NH4Cl-solution (35 mL) and EtOH (170 mL) was refluxed for 30 min. The mixture was concentrated, treated with water and the pH was adjusted to ˜8. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was treated with PE and the sub-title compound was filtered off. Yield: 2.7 g (88%).
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23].C[O-].[Na+]>CO>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:5]2[C:4]([OH:18])=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:6]=2[OH:8])=[CH:16][CH:15]=1
Reactant: CCCC(=N)N
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(O)c(-c2ccc(C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of diethyl(4-methylphenyl)malonate (9.45 g) and butyramidine hydrochloride (5.00 g) in methanol (25 ml) is added 28% sodium methoxide (19.67 g) under ice-cooling, and the mixture is stirred at room temperature overnight. After the reaction is complete, the reaction solution is concentrated to the half volume thereof, and the resultant is diluted with water. The mixture is acidified with 10% hydrochloric acid, and the precipitated crystals are collected by filtration, washed, and dried to give 5-(4-methylphenyl)-4,6-dihydroxy-2-n-propylpyrimidine (5.17 g) as crystalline powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:8]1([C:16]2[CH:11]=[CH:12][CH:13]=[C:14]([C:30]3[CH:29]=[N:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:15]=2)[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:10]([NH2:17])=[N:9]1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: NC1=NC(c2cccc(-c3cncc(F)c3)c2)(c2ccncc2F)c2ccccc21
Yield: 57 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Scheme #12, I) as described in Scheme #10, D in 57% yield using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. 1H NMR (DMSO-d6) δ 8.58-8.52 (m, 1 H), 8.49 (d, J=2.78 Hz, 1 H), 8.37 (d, J=2.78 Hz, 1 H), 8.27 (d, J=4.80 Hz, 1 H), 7.88-7.82 (m, 1 H), 7.81-7.72 (m, 2 H), 7.60-7.53 (m, 1 H), 7.51-7.40 (m, 3 H), 7.35 (t, J=7.71 Hz, 1 H), 7.30-7.25 (m, 1 H), 7.21 (dd, J=6.82, 5.05 Hz, 1 H), 6.95 (br s, 2 H), 1.84 (s, 1.4 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46]([CH3:49])[CH2:47]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:47][CH:46]([CH3:49])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC1CS/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C(C)C)C1
Temperature: 80 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and potassium carbonate (105 mg, 0.763 mmol) in butanone (4 ml) was added 1-bromo-3-chloro-2-methylpropane (39.0 mg, 0.229 mmol). The reaction was heated to 80° C. overnight. The reaction mixture was then diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a light yellow solid as a mixture of rotational diastereoisomers: mp 186-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=3.6 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.84-7.77 (m, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.38 (d, J=9.0 Hz, 3H), 7.32 (td, J=7.5, 1.4 Hz, 1H), 7.26 (s, 1H), 7.17 (t, J=7.1 Hz, 1H), 3.69-3.26 (m, 1H), 3.55-3.37 (m, 1H), 3.18-2.98 (m, 2H), 2.93-2.80 (m, 1H), 2.47 (d, J=35.9 Hz, 1H), 1.31-1.12 (m, 9H); ESIMS m/z 580 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH2:74]C)[CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-ethylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-175).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[C:21](=[O:22])[N:20]2[CH2:23][CH2:24][C@@H:25]([C:27]([F:30])([F:29])[F:28])[NH:26][C:19]2=[N:18][C:17]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(#N)C>[CH2:7]([N:26]1[C:19]2=[N:18][C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:16]([F:15])[C:21](=[O:22])[N:20]2[CH2:23][CH2:24][C@H:25]1[C:27]([F:28])([F:30])[F:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(F)c(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1c(F)c(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
4 g of caesium carbonate and 796 mg of benzyl bromide are added to a suspension of 1 g of (8S)-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one in 11.8 ml of acetonitrile. After stirring overnight at a temperature in the region of 20° C., the suspension obtained is filtered and the resulting filtrate is concentrated to dryness under reduced pressure. The oily yellow residue is purified on a silica column (eluent: CH2Cl2/MeOH 98/02). The fractions of interest are combined and concentrated to dryness under reduced pressure. The residue is taken up with diethyl ether, spin-filter-dried and then dried under vacuum. 600 mg of (8S)-9-benzyl-3-fluoro-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-hydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:40]2[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=2)OCCCO1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.4 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197-198° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:27][N:26]([C:29](N2C=NC=C2)=[O:30])[CH:25]=1.CNC>CC#N>[CH3:25][N:26]([CH3:27])[C:29]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1)=[O:30]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1CC(=O)c2sc(N)nc2C1
Agent: CNC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CC(=O)c2sc(NC(=O)N(C)C)nc2C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (30.0 g, 0.165 mol) in MeCN (750 mL) are added DBU (75.2 g, 0.495 mol) and CDI (80.1 g, 0.495 mol) at RT. The reaction mixture is stirred at 110° C. overnight. Dimethylamine (93.5 g, 1.15 mol) and another portion of DBU (175 g, 1.15 mol) are added to the mixture at RT and the stirring is continued overnight at 110° C. After cooling to RT, the reaction mixture is evaporated in vacuo and the residue is poured into ice water. The reaction mixture is treated with HCl (6 M) to pH to 5. The aqueous mixture is extracted with EtOAc (3×300 mL). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is recrystallized from hexane to give 1,1-dimethyl-3-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea (32.1 g, 77% yield).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:3][CH2:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][CH:6]=2)[CH2:21][CH2:22]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Nc1ncc(CCCl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(CCN2CCN(c3ccccn3)CC2)s1
Reaction time: 18 h

Procedure:
A mixture of 5.84 g of 5-(2-chloroethyl)-2thiazolamine, monohydrochloride (Example C), and 5.27 g of 1-(2-pyridyl)piperazine in 100 ml of dimethylformamide containing 12.3 g of sodium bicarbonate is stirred at 80°-90° C. for 18 hours. The mixture is filtered and the filtrate concentrated to dryness. Chromatography (medium-pressure liquid chromatography, silica gel, 5% methanol-95% chloroform) of the resulting oil affords 5-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-2-thiazolamine as a tan solid; mp 158°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].P([O-])(OCC)(SCC)=[S:22].C(O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]([NH2:12])=[S:22]
Reactant: CCOP([O-])(=S)SCC
Reactant: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 110 °C
Yield: 85.2 %

Procedure:
(2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile (50.0 g, 180 mmol), diethyl dithiophosphate (134 mL, 719 mmol), isopropanol (50 mL) and water (40 mL) were mixed together and the mixture was heated in an oil-bath (temp. setting at 110° C.) for 3 h. After cooling to 0° C., 5% Na2CO3 aqueous solution (500 mL) was added slowly and then solid Na2CO3 (25 g) was added portionwise. The mixture was extracted with EtOAc (1 L) and the EtOAc layer was washed with sat. NaHCO3 aqueous solution, water (×2) and brine, dried over MgSO4 and evaporated under reduce pressure. The resulting solid was purified by recrystalization from isopropanol to give pure (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyrarnide (47.9 g, 85%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:8]1[CH:9]=[C:2]([C:17]#[N:18])[CH:3]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C#N)c(F)c1
Temperature: 90 °C

Procedure:
To a solution of 4-bromo-6-fluorobenzonitrile (5 g, 25 mmol) in anhydrous DMF (20 mL) was added Zinc cyanide (1.75 g, 14.9 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.6 g, 0.519 mmol). The reaction mixture was heated overnight under argon at 90° C. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (150 mL) and extracted with water 50 mL, 2×30 mL, brine (30 mL), then dried over anhydrous sodium sulfate. After rotary evaporation of most solvent, the concentrated solution was loaded onto a silica column and eluted with EtOAc/Hexane (1:6). A white solid was obtained (3.73 g). 1H-NMR (300 MHz, CDCl3) δ 7.80 (m, 1H), 7.58 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[OH:22])=[CH:5][CH:4]=1)#[N:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 443 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:26][C@@H:27]1[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]1>C1COCC1>[CH3:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:25][CH:24]=1)[C:16](=[O:17])[N:26]([C@@H:27]1[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]1)[CH2:21]2
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@H]1COCC[C@@H]1O)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.20 g) in THF (4.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g), and the mixture was stirred at room temperature for 4 hr under argon atmosphere. The reaction mixture was concentrated, and the residue was diluted with acetic acid (4.00 mL). Sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@H:15]1[C@:19]2([CH3:33])[CH2:20][C@H:21]3[C@H:30]([CH2:31][C@H:18]2[CH2:17][CH2:16]1)[C@@H:29]1[C@H:24]([CH2:25][C:26](=[O:32])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3.CC(O)C>CC(C)=O>[CH3:33][C@:19]12[C:15](=[O:14])[CH2:16][CH2:17][C@@H:18]1[CH2:31][C@H:30]1[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:29]1[CH2:28][CH2:27][C:26](=[O:32])[CH2:25]3)[CH2:20]2
Reactant: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
Jones reagent was added to a solution of compound 37 (605 mg, 2.2 mmol) in acetone (40 mL) at 0° C. until a brown-yellowish color persisted. After 10 min, 2-propanol (1.0 mL) was added to consume excess oxidant. Brine (50 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give compound 38 (580 mg, 96%) as a white solid: [α]D25 −13.1 (c 0.145, CHCl3); 1H NMR (CDCl3) δ 0.81 (s, 3H); 13C NMR (CDCl3) δ 220.1, 211.0, 48.2, 47.8, 47.6, 45.6, 45.4, 43.5, 40.9, 38.9, 37.6, 3.54, 34.0, 33.4, 29.9, 28.7, 23.8, 13.4; IR νmax 1716, 1715 cm−1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:28]([N:24]1[C:23]([C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([CH:9]5[CH2:8][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:10]5)[CH:32]=[CH:31][C:14]=4[C:15]=3[N:16]=2)=[N:27][CH:26]=[N:25]1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)CO)C3)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester (147 mg, 0.31 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen was treated dropwise with a 1M solution of LiAlH4 in THF (0.47 mL, 0.47 mmol) and the mixture was stirred for 15 minutes then allowed to warm to RT. After 1.5 hours the mixture was cooled to 0° C. and quenched by cautious addition of water. EtOAc was added and the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (20 mL) and treated with 4N HCl/dioxan (1 mL). The resulting solid was filtered off, washed with ether and dried to give 427 (142 mg, quant.). LCMS: RT=7.54 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 10.61 (1H, s), 8.32 (1H, d, J=8.21 Hz), 8.07 (1H, s), 7.22-7.16 (1H, m), 7.06 (1H, d, J=1.80 Hz), 5.81-5.72 (1H, m), 4.55 (1H, td, J=10.55, 4.79 Hz), 4.38-4.26 (3H, m), 4.16-3.92 (3H, m), 3.46-3.37 (5H, m), 1.53-1.48 (6H, m), 1.27-1.14 (6H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][C:13]#[CH:14])[CH:7]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:6][CH2:5]2>BrC1C=CC=CC=1>[Br:1][C:2]1[C:10]2[O:11][CH2:12][CH:13]=[CH:14][C:9]=2[C:8]2[CH:7]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C#CCOc1cc2c(cc1Br)CCC2CCNC(=O)CC
Solvent: Brc1ccccc1
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)C=CCO3
Yield: 85 %

Procedure:
A solution of N-[2-(5-bromo-6-(2-propynyl)oxyindan-1-yl)ethyl]propionamide (2.9 g, 8.4 mmol.) in bromobenzene (30 mL) was stirred for 18 hours in a sealed tube at 200° C. The reaction mixture was cooled and, then, the solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 2.5 g, 85%).