Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][C:19]\2=[O:20])=[N:9]1.[BH4-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18][CH:19]\2[OH:20])=[N:9]1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2ccccn2)n1
Agent: [BH4-]
Agent: [Na+]
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2ccccn2)n1

Procedure:
Following a procedure similar to that described in Example 146-(b), (E)-3-({1-[(2-pyridyl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (1.8 g) was treated with sodium borohydride to afford (E)-3-({1-[(2-pyridyl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol as a yellow amorphous solid in a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH2:34])=[CH:29][C:28]=3[O:35][C:36]([F:39])([F:38])[F:37])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][N:46]=1>>[CH3:1][O:2][C:3](=[O:40])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH:34][C:51]([C:48]4[CH:47]=[N:46][C:45]([F:44])=[CH:50][CH:49]=4)=[O:52])=[CH:29][C:28]=3[O:35][C:36]([F:38])([F:39])[F:37])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(N)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(F)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-amino-5′-fluoro-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (50 mg, 0.09 mmol, Preparation 43) in DCM (0.6 mL, 9 mmol) was slowly added 2-fluoropyridine-5-carbonyl chloride (10 mg, 0.09 mmol;) and the reaction mixture was stirred at room temperature for 5 min and then concentrated to provide a colored solid.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[C:12]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][CH:22]2[CH2:24][CH2:23]2)=[CH:14][CH:13]=1.C(N(CC)CC)C.CCCCCCC.C(OCC)(=O)C>O1CCCC1>[C:12]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH:22]2[CH2:24][CH2:23]2)[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])=[CH:14][CH:13]=1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: c1ccc(-c2ccc(OCCNC3CC3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)N(CCOc1ccc(-c2ccccc2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
At ambient temperature, a solution of 230 mg (1.29 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a mixture of 300 mg (1.18 mmol) of N-[2-(biphenyl-4-yloxy)ethyl]cyclopropanamine as its hydrochloride salt and 250 mg (2.48 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 2 hrs at 80° C. The solvent is removed under vacuum and 10 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×25 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried of magnesium sulfate to gave after concentration 750 mg of a yellow oil. Column chromatography (gradient heptane/ethyl acetate) yielded 220 mg (47% yield) of N-[2-(biphenyl-4-yloxy)ethyl]-N-cyclopropyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide as a colourless oil (M+H=394).
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:26]=[N+:27]=[N-:28])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[O:12]1)(=[O:8])[O:5]CC)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>CC#N>[N:26]([C:11]1([CH:10]=[CH:9][P:4](=[O:3])([OH:8])[OH:5])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[O:12]1)=[N+:27]=[N-:28]
Reactant: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C(O)C1O)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: [N-]=[N+]=NC1(C=CP(=O)(O)O)OC(n2ccc(=O)[nH]c2=O)C(O)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Compound 48.5 (119 mg, 0.28 mmol) was dissolved in 2.6 mL CH3CN, treated with 2,6-lutidine (0.1 mL) and TMSBr (0.2 mL). The mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was coevaporated with saturated NH4OH three times and the residue was subjected to a reverse phase HPLC to give compound 48.6 (100 mg, 92% yield). 1H NMR (D2O, 300 MHz) 7.45 (d, J=8.1 Hz, 1H), 6.22 (app d, J=8.7 Hz, 1H), 6.16 (app d, J=5.7 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 5.71 (d, J=8.1 Hz, 1H), 4.31 (m, 1H), 4.24 (m, 1H); 31P NMR (D2O 121.4 MHz) 7.3; MS (ESI) m/z 359 [M−2H]+.
Reaction SMILES: C1(SCC2[C:18]3[C:13](=[CH:14][CH:15]=[C:16](C4C=CC=CC=4OC)[CH:17]=3)[NH:12]C(C)(C)C=2)CCCCC1.Br[CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])[CH:39]=2)[NH:34][C:33]([CH3:50])([CH3:49])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C1(S)CCCCC1>>[CH3:48][O:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:50])([CH3:49])[CH:32]=[C:31]2[CH2:30][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSC1CCCCC1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SC1CCCCC1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Cyclohexylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 27 μL of cyclohexylmercaptan reacted to give 5 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Intermediate 1 (8.9 g, 30.56 mmoles) was taken in a RB flask and to this acetic anhydride (59 ml) and sodium acetate (17.5 g, 213 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (9.4 g, 97% yield). MP: 119-121° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35 (d, J=2.4 Hz, 1H), 7.75 (dd, J=11.3, 2.4 Hz, 1H), 7.46 (t, 2H), 7.39 (d, J=7.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.28 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)O)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
A solution of 28 (304 mg, 1 mmol) in EtOAc (20 mL) was hydrogenated at 60 psi in the presence of 10% Pd-C (60 mg) for 12 h. The solution was filtered, and solvents were evaporated. The crude product was purified by crystallization from EtOAc and hexane (183 mg, 60%); mp 66°-67° C.; 1H NMR (CDCl3, 200 MHz) δ7.12 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.39 (s, 2H), 3.87 (s, 2H), 3.82 (s, 3H), 3.81 (s, 6H), 3.79 (s, 3H); CIMS (isobutane) m/e 289 (MH+, 100). Anal. (C17H20O4) C, H.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[Br:13][C:14]1[C:15](=O)[O:16][C:17](=[O:19])[CH:18]=1>O>[Br:13][C:14]1[C:15](=[O:16])[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH:10][C:17](=[O:19])[CH:18]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(Cn2[nH]c(=O)cc(Br)c2=O)cc1
Temperature: 100 °C

Procedure:
(4-methoxybenzyl)hydrazine hydrochloride (2.132 g, 11.30 mmol) and 3-bromofuran-2,5-dione (2 g, 11.30 mmol) in water (20 ml) was stirred and heated at 100° C. overnight. The mixture was cooled to room temperature and filtered to collect the solid. The solid was triturated with a mixture of ethyl acetate and ethyl ether (1/4) and the mixture was filtered. The insoluble residue was 4-bromo-1-(4-methoxybenzyl)-1,2-dihydropyridazine-3,6-dione. LRMS m/z (M+H) 311.0 found, 311.0 required. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (Petroleum ether: ethyl acetate=1/1)) to give 5-bromo-1-(4-methoxybenzyl)-1,2-dihydropyridazine-3,6-dione. LRMS m/z (M+H) 311.0 found, 311.0 required.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[CH3:13][NH:14][NH2:15].Cl.C(Cl)Cl>CCO.O>[CH3:13][N:14]1[C:6]([NH2:7])=[CH:5][C:4]([C:3]([CH3:10])([CH3:9])[C:2]([F:1])([F:11])[F:12])=[N:15]1
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1nc(C(C)(C)C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) in EtOH (10 mL) was added methylhydrazine (3.33 g, 28.9 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column). All fractions found to contain product by TLC (EA:PE=1:2, Rf=0.2) were combined and concentrated to yield a white solid of 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.293 mmol, 41.1% yield): 1H NMR (400 MHz, CD3OD): δ 5.48 (s, 1H), 3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[C:19]1([CH:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[C:19]1([CH:25]([N:27]2[CH2:28][CH2:29][N:30]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: CC(c1ccccc1)N1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccc1)N1CCN(Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2)CC1
Reaction time: 24 h
Yield: 23.1 %

Procedure:
Using a method similar to Example 332, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.307 g, 1.27 mmol), 1-(1-phenylethyl)piperizine (0.365 g, 1.92 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (10 mL), after 1 d, provides 0.122 g (23%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C25H29N4O2 417.2291, found 417.2298; 1H NMR (DMSO-d6): 8.62 (d, 1H, J=2.0 Hz), 8.26 (dd, 1H, J=2.4, 8.8 Hz), 8.01 (s br, 1H), 7.46 (s br, 1H), 7.36-7.28 (m, 6H), 7.27-7.21 (m, 1H), 7.12-7.05 (m, 3H), 3.42 (s, 2H), 3.39 (q, 1H, J=6.8 Hz), 2.51-2.25 (s br, 8H), 1.29 (d, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:14])=O>>[C:1]([Cl:14])(=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC=CCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCC=CCC(=O)Cl

Procedure:
A mixture of 22 g. of 3-nonenoic acid and 100 ml. of thionyl chloride is stirred at room temperature for about an hour, then 150 ml. of 1:1 ether-benzene mixture is added. The solvents are removed by evaporation under reduced pressure, then another 150 ml. of 1:1 ether benzene mixture is added to the residue, and removed by evaporation under reduced pressure, leaving a residue comprising 3-nonenoyl chloride. This residue is then dissolved in 30 ml. of benzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C: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)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cn2)CC1
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a stirred mixture of tert-butyl 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.2, 500 mg, 1.65 mmol, 1.00 equiv) in pyridine (20 mL) was added dropwise phosphoryl trichloride (2.5 g, 16.34 mmol, 9.90 equiv) at 10-15° C. The resulting solution was stirred for 18 h at 15˜20° C. The reaction was then carefully quenched by the addition of 20 mL of water and extracted with 3×100 mL of ethyl acetate. The combined organic phases were washed with 2×50 mL of aqueous HCl (1 M) followed by 1×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100 to 1:7) as eluent to yield 0.3 g (64%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].I[CH2:15][CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:15][CH3:16])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CCNC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)CNC1CCCC1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a mixture of 1.0 g (0.0054 mole) of 3-cyclopentylamino-propanoic acid ethyl ester, 0.842 g (0.00542 mole) of iodoethane and 15 mL of dry tetrahydrofuran, at −78 degrees, was added 11.4 mL (0.0114 mole) of a 1M solution of lithium bis(trimethylsilyl)amide in hexanes over 5 minutes. The mixture was stirred for one hour at −78 degrees, then the cooling bath was removed and the mixture stirred overnight at room temperature, and then poured into ice water containing 5 mL of 1M sodium hydroxide solution. The mixture was extracted with ether, and the ether extract washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.5125 g of (rac)-2-cyclopentylaminomethyl-butanoic acid ethyl ester, which was used without further purification in subsequent steps.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:21][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:22][C:23]#[N:24].[K+].BrBr>S([O-])([O-])(=O)=O.[Cu+2]>[ClH:20].[ClH:1].[NH2:24][C:23]1[S:22][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[CH2:9][CH2:8][C:7]=3[S:21][C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: Nc1cc2c(s1)CCN(Cc1ccccc1Cl)CC2
Agent: [Cu+2]
Agent: BrBr
Agent: Cl
Product: Nc1nc2sc3c(c2s1)CCN(Cc1ccccc1Cl)CC3

Procedure:
This compound was prepared from 2-amino-6-(2-chlorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine or copper sulfate as oxidizing agent analogous to Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[S:18][C:19]([CH3:22])=[CH:20][N:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:22][C:19]1[S:18][C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)=[N:21][CH:20]=1
Reactant: Cc1cnc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)s1
Agent: Cl
Product: Cc1cnc(-c2ccc3c(c2)CNC3)s1

Procedure:
Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiazol-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown gum. MS (m/e): 217.0 ([M+H]+, 100%)
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([Cl:29])=[O:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
A mixture of 21.7 g of p-tetradecyloxyphenylacetic acid and 11.85 g of oxalyl chloride, 45.5 mg of N,N-dimethylformamide and 250 ml of methylene chloride is stirred at ambient temperature for 24 hours. The solvent is removed by evaporation and the residue is dissolved in ether and filtered through diatomaceous earth. The filtrate is evaporated to give 22.3 g of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:8])([O-:3])=[O:2]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc([N+](=O)[O-])c1
Yield: 90.9 %

Procedure:
0.388 g (0.0021 mol) of 3-nitro-benzoyl chloride were dissolved in 20 ml of toluene under argon and treated while stirring with 0.5 g (0.0026 mol) of 1-benzyl-4-hydroxy-piperidine and 0.643 ml (0.0046 mol) of triethylamine. After boiling at reflux for 2 hrs. the suspension was filtered and the filtrate was completely freed from solvent. The residue was chromatographed over silica gel with ethyl acetate/hexane 1:2 as the eluent. 0.65 g (92%) of 1-benzyl-piperidin-4-yl 3-nitro-benzoate was obtained as a yellow oil. MS: mele (% basic peak)=340 (C19H20 N2O4+, 27), 263 (25), 173 (36.5), 150 (14.5), 91 (100), 82 (100).
Reaction SMILES: [CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:23]3[S:24][C:25]([F:28])=[CH:26][CH:27]=3)([N:7]([C:12]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[S:13])[O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]>[Zn].C(O)(=O)C>[CH2:1]([N:4]1[CH2:11][CH:10]([CH2:9][OH:8])[C:6]([NH:7][C:12]([NH:14][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:13])([C:23]2[S:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccc(F)s2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCN1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccc(F)s2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.1 %

Procedure:
To N-[5-allyl-6a-(5-fluoro-2-thienyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-1-carbothioyl]benzamide (6.91 g, 16.5 mmol) is added acetic acid (110 mL) followed by powdered zinc (10.8 g). The resulting gray mixture is rapidly stirred at room temperature for 40 minutes. The mixture is filtered through diatomaceous earth while rinsing with methanol (approximately 250 mL). The filtrate is concentrated under reduced pressure, diluted with methanol (200 mL), and concentrated under reduced pressure. The residue is dissolved in dichloromethane (300 mL) and treated with 1 M potassium carbonate solution (200 mL). The resulting emulsion is filtered through diatomaceous earth while rinsing with water (approximately 40 mL) and dichloromethane (200 mL). The phases are separated and the aqueous phase is further extracted with dichloromethane (100 mL). The combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6.65 g, 96%). ES/MS (m/e): 420 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:31])=[C:17]([C@:19]2([CH3:30])[CH2:24][S:23](=[O:26])(=[O:25])[C:22]([CH3:28])([CH3:27])[C:21]([NH2:29])=[N:20]2)[CH:18]=1>>[NH2:29][C:21]1[C:22]([CH3:27])([CH3:28])[S:23](=[O:25])(=[O:26])[CH2:24][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:31])([CH3:30])[N:20]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Reactant: COc1cnc(C(=O)O)cn1
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)CS(=O)(=O)C(C)(C)C(N)=N3)c2)cn1
Yield: 65.8 %

Procedure:
Prepared from commercially available 5-methoxypyrazine-2-carboxylic acid (CAS-no. 40155-42-8) (43.2 mg, 281 μmol, Eq: 1.2) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (70 mg, 234 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (67 mg, 154 μmol, 65.8% yield) as a white foam. MS (ISP): m/z=436.5 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH3:14])=[CH:3][C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>CCOCC>[CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH3:14])=[CH:3][CH2:4][OH:5]
Reactant: CCC(C)=CCCCC(C)=CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(C)=CCCCC(C)=CCO
Reaction time: 1 h

Procedure:
A solution of 2 g. of methyl 3,8-dimethyldeca-2,7-dienoate in 20 ml. of dry ether is added with stirring to 0.4 g. of lithium aluminum hydride covered in ether at 0°. After about one hour, 2.5 ml. of acetic acid is added. The mixture is washed with ice water and the ether phase dried and evaporated to yield 3,8-dimethyldeca-2,7-dien-1-ol which is treated with phosphorus tribromide to yield 1-bromo-3,8-dimethyldeca-2,7-diene.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1
Reactant: C1=COCCC1
Reactant: O=C1CC(O)CO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC(OC2CCCCO2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of 4-hydroxy-dihydrofuran-2(3H)-one (10 g, 0.1 mol, Alfa) and dihydropyran (12.5 g, 0.15 mol, Alfa) in 250 mL of dry CH2Cl2 was added PPTS (2.5 g 0.01 mol), and the reaction mixture was stirred at rt overnight. The reaction mixture was washed with brine and extracted with CH2Cl2 (100 mL×3), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (3:1 (v/v) EtOAc/n-Hexane) to give the title compound as colorless oil (15.6 g, 68%).