Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: CCCc1cc(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(O)CCC>CN(C=O)C.CO>[N:21]1([C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:19][O:18][CH2:23][CH2:22]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)Nc1ccc(-c2ccnc(Cl)n2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCCCO
Product: CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A flask was charged with C1 (500 mg, 2.0 mmol), 4-morpholinoaniline H (540 mg, 3.0 mmol) and nBuOH (10 mL). The flask was immersed in a 180° C. oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the title compound (18).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[O:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CO)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation according to Preparation 22 using [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methanol (0.4 g, 1.65 mmol), DCM (25 ml), p-toluenesulfonyl chloride (0.47 g, 2.5 mmol), TEA (0.28 ml, 2.0 mmol) and 4-DMAP (0.24 g, 2.0 mmol) stirred for overnight at room temperature. Yield: 0.59 g. MS m/z (rel. intensity, 70 eV) 419 (62), 416 (14), 415 (25), 414 (bp), 397 (M+1, 39).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1.[NH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][CH2:22][NH:21][C:14]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]1[O:5][C:4]([CH2:3][NH:2][CH3:1])=[CH:8][CH:7]=1)=[CH:15][N+:16]([O-:18])=[O:17])[CH3:35]
Reactant: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)o1

Procedure:
a mixture of N-methyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine (1.6 g) (prepared from the oxalate salt) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.15 g) was heated at 98°-100° for 3 hours. The oily product was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound as a hydrate as an amber oil (2.12 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1B(O)O)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Temperature: 100 °C
Yield: 40.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 118b (103 mg, 0.33 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (136 mg, 0.33 mmol), PdCl2(dppf) (27 mg, 0.033 mmol), K3PO4 (171 mg, 0.66 mmol), sodium acetate (54 mg, 0.66 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 118c as a yellow solid (80 mg, 41%). MS-ESI: [M+H]+ 600.2
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH3:10]>>[CH2:19]([O:18][C:16]([CH:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:17])[CH3:20]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1ccc(F)cc1
Product: CCOC(=O)CC(Nc1ccc(F)cc1)C(=O)OCC

Procedure:
A solution of 10.0 g (0.09 mole) 4-fluoroaniline 7 and 8.0 g (0.047 mole) diethylacetylene dicarboxylate 8 is stirred at room temperature for 72 hours. The crude product is purified by flash chromatography using silica gel eluted initially with ethyl acetate:hexane (1:4) and finally with ethyl acetate. The fractions containing the product are combined and concentrated under reduced pressure to give 9 as a yellow oil.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[CH:14].[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[C:14][C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: C#Cc1ccc(-c2ccccc2)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Cl
Temperature: -60 °C

Procedure:
13.8 mL (22.1 mmol) of butyllithium solution (1.6M in hexane) are added dropwise to a solution of 4.7 g (22.1 mmol) of 3-chloro-4-ethynylbiphenyl in 100 mL of absolute THF at −10° C. to −20° C. and after five minutes cooled to −60° C. At this temperature dry ice is added batchwise to the reaction mixture and it is slowly allowed to come up to ambient temperature. Then the solvent is evaporated down and the residue is extracted between ethyl acetate and 1M hydrochloric acid. The organic phase is dried, the desiccant filtered off, and the solvent concentrated by evaporation. The residue is stirred with petroleum ether, suction filtered, and dried at 80° C. in the circulating air dryer. Yield: 4.8 g (85% of theory); C15H9ClO2 (M=256.68); calc.: molecular ion peak (M+H)+: 257/259 (Cl); found: molecular ion peak (M+H)+: 257/259 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol/glacial acetic acid (90:10:0.1)).
Reaction SMILES: [C:1]([NH:5][CH:6](O)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:9](=[S:11])=[S:10]>>[C:1]([N:5]1[CH2:6][CH2:7][S:11][C:9]1=[S:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: S=C=S
Reactant: CC(O)NC(C)(C)C
Product: CC(C)(C)N1CCSC1=S

Procedure:
Similarly to Example 1, 256 g/h of N-t-butylaminoethanol are reacted with 333 g/h of carbon disulphide to form 382 g/h of N-t-butylthiazolidine-2-thione having a melting point of from 69° to 70° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.CCCCCC>[Si:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1cc(Br)c2occc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 231 %

Procedure:
A mixture of 0.12 gm (0.52 mmol) 5-hydroxymethyl-7-bromobenzofuran 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol), 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol) tert-butyldimethylsilyl chloride in 1 mL dimethylformamide was stirred at room temperature for 18 hours. The reaction mixture was diluted with hexane and washed well with water. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.41 gm (82%) of 5-tert-butyldimethylsilyloxymethyl-7-bromobenzofuran. This material was reacted essentially as described in EXAMPLE 1 to provide 0.085 gm (24%) 1-(5-tert-butyldimethylsilyloxy-methylbenzofur-7-yl)-2-aminopropane. This material was treated with tetrabutylammonium fluoride in tetrahydrofuran for 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed well with water. The remaining organics were concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 2% methanol saturated with ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 0.028 gm (50%) of 1-(5-hydroxymethylbenzofur-7-yl)-2-aminopropane. The title compound was prepared by reacting this amine with hydrochloric acid.
Reaction SMILES: C(OC1C=C(C=CC=1C)CN1CCC(NC2C=C(C=CN=2)C#N)CC1)C.Cl.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:31][CH2:30]1.[CH:44]([O:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([O:56][CH:57]([CH3:59])[CH3:58])[CH:55]=1)[CH:51]=O)([CH3:46])[CH3:45]>>[CH:57]([O:56][C:54]1[CH:53]=[C:50]([CH:49]=[C:48]([O:47][CH:44]([CH3:46])[CH3:45])[CH:55]=1)[CH2:51][N:29]1[CH2:30][CH2:31][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:33][CH2:34]1)([CH3:58])[CH3:59]
Reactant: N#Cc1ccnc(NC2CCNCC2)c1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Agent: Cl
Product: CC(C)Oc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)cc(OC(C)C)c1

Procedure:
The title compound was prepared in analogy to the synthesis of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile (example 189) from 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (intermediate B15) and 3,5-diisopropoxy-benzaldehyde (intermediate E4) in a yield of 3.6 mg (5%). MS (ISP): 409.5 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:41]=[C:24]4[C:25]([C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=5[O:39][CH3:40])=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:40][O:39][C:30]1[CH:31]=[CH:32][C:33]([C:35]([F:36])([F:38])[F:37])=[CH:34][C:29]=1[C:25]1[C:24]2[N:23]([N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[N:41]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12

Procedure:
[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.342 g, 0.603 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.239 g, 85%). MP=104-108° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.55 (d, 2H), 7.35 (d, 1H), 7.05 (m, 3H), 3.85 (s, 3H), 3.00 (m, 2H), 2.55 (br m, 4H), 1.65 (m, 2H), 1.50 (m, 2H): MS=468 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:19]1([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 90 °C
Yield: 81.1 %

Procedure:
A stirred suspension of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (5.6 g, 19 mmol), cyclopropyl boronic acid (2.09 g, 23.3 mmol) Pd(dppf)Cl2 (1.24 g, 1.5 mmol) and 2M aqueous cesium carbonate (30 mL, 60 mmol) in toluene (20 mL) was degassed before being heated at 90° C. under an argon atmosphere for 2.5 hours. The reaction mixture was allowed to cool to room temperature before filtering through a pad of Celite®, washing with ethyl acetate. The filtrate was washed (water, brine), and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in pentane) to give the title compound as a yellow solid (2.79 g, 81%). 1H NMR (DMSO-d6, 400 MHz) 8.03 (1H, t, J=8.39 Hz), 7.28 (1H, dd, J=13.19, 1.91 Hz), 7.16 (1H, dd, J=8.61, 1.90 Hz), 2.14-2.05 (1H, m), 1.21-1.05 (2H, m), 0.92-0.82 (2H, m).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.C1CCN2C(=NCCC2)CC1.[C:37]([O:46][CH3:47])(=[O:45])/[CH:38]=[CH:39]/[CH2:40][C:41]([O:43][CH3:44])=[O:42]>C(OCC)(=O)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:39]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:38][C:37]([O:46][CH3:47])=[O:45])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: COC(=O)/C=C/CC(=O)OC
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65° C. and dimethyl (2E)-pent-2-enedioate (16 mL, 0.12 mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HCl, brine, dried over magnesium sulfate, and then concentrated to give a dark oil. The viscous oil was triturated with ethyl ether 3×500 mL to give a dark precipitate. The oil was taken up in ethyl acetate to form a solid. The solids were collected, washed with ethyl ether and dried to give dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate as a white powder (29.5 gm, 64%), LC/MS (M+H)+: 474, 1H NMR (DMSO-d6) δ 9.1 (s, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42 (d, 1H), 5.78 (s, 2H), 5.27 (m, 1H), 3.65 (m, 8H), 3.15 (m, 4H), 0.95 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1>CCOC(C)=O.ClCCl>[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][N:58]([C:12](=[O:14])[CH2:11][C:7]5[N:6]=[C:5]6[O:4][CH2:3][CH2:2][O:1][C:10]6=[CH:9][CH:8]=5)[CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1nccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)n1
Reactant: O=C(O)Cc1ccc2c(n1)OCCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4ccc5c(n4)OCCO5)CC3)C2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl) acetic acid (SM-1aj, 27.27 g, 139.73 mmol), dichloromethane (495 mL), and triethylamine (67.74 mL, 468.03 mmol) was added 1,1′-carbonyldiimidazole (22.66 g, 139.73 mmol) at 20° C. and the resulting mixture was heated to 40° C. and stirred for 2 hours. The reaction was charged with 2-[(R)-5-(2-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1 h, 49.50 g, 121.51 mmol). The resulting mixture was stirred at 40° C. for 2 hours, monitoring by HPLC for consumption of amine starting material. The reaction temperature was adjusted below 25° C. and charged with water (1500 mL) and stirred for 5 min. The layers were separated and the organic layer was concentrated to dryness and backfilled with EtOAc (1000 mL) and further concentrated to approximately 300 mL. The resulting thick solution was cooled to 20° C. and stirred until crystals formed. The very thick mixture was diluted with EtOAc (1000 mL) and stirred for 5 min, filtered and dried under vacuum at 45° C. to afford the title compound (21.8 g, 35%). MS (ES+) 512.5 (M+H)+. 1H NMR (CDCl3) δ 1.64-1.75 (m, 4H), 1.90-2.00 (m, 1H), 2.14-2.23 (m, 1H), 2.81 (s, 3H), 2.85-2.94 (m, 1H), 3.08-3.20 (m, 5H), 3.45-3.57 (m, 4H), 3.77 (s, 2H), 3.98 (dd, 1H), 4.22-4.28 (m, 2H), 4.41-4.46 (m, 2H), 6.91 (d, 1H), 7.15 (d, 1H), 7.38 (d, 1H), 7.48 (d, 1H), 7.86 (d, 1H), 7.96 (s, 1H), 8.65 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]([Cl:21])=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:11][C:12]1[C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]([Cl:21])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(Cl)c2occc12)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Cl)c2occc12
Yield: 66.6 %

Procedure:
A mixture of 2-(7-chloro-benzofuran-4-ylmethyl)-malonic acid diethyl ester (2.47 g) and sodium chloride (0.656 g) in DMSO (12 ml) and water (0.5 ml) was heated at 200° for 4 h under nitrogen. The cooled mixture was partitioned between water (80 ml) and ether (3×50 ml) and the combined organic extracts washed with brine (3×50 ml) and dried (MgSO4). The solvent was evaporated to give the title compound as a brown oil (1.28 g)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[NH2:12])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(F)(F)F)cc2N)CC1
Temperature: 25 °C

Procedure:
Example 18 was prepared in accordance to a procedure described in Collins, et. al., Tetrahedron, 48, No. 37, pp 7887-7898, 1992. To a solution of 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added 1-Methyl-piperazine (0.64 mL, 5.74 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH2Cl2 and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1cccnc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn2c(c1O)C(=O)N(C)CC2c1cccnc1
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-4-oxo-7-pyridin-3-yl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.48 g, 1.2 mmol) in MeOH (25 mL) was added 10% palladium on carbon (60 mg). The mixture was stirred under an atmosphere of hydrogen gas for 2 hours. The reaction was then filtered through celite, and the filtrate solvent was removed in vacuo to give the product as a gum. ES MS (M+1)=303.
Reaction SMILES: O1CC=CC2C=CC3C(C1=2)=CC=CC=3.[O:15]1[CH:17]2[C:18]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:19]=3[O:20][CH2:21][CH:16]12.[CH:30]([NH2:33])([CH3:32])[CH3:31]>C(O)C>[CH:30]([NH:33][C@H:17]1[C@H:16]([OH:15])[CH2:21][O:20][C:19]2[C:22]3[C:27]([CH:28]=[CH:29][C:18]1=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:32])[CH3:31]
Reactant: c1ccc2c3c(ccc2c1)C1OC1CO3
Reactant: CC(C)N
Agent: C1=Cc2ccc3ccccc3c2OC1
Solvent: CCO
Product: CC(C)N[C@@H]1c2ccc3ccccc3c2OC[C@H]1O

Procedure:
2H-Naphtho[1,2-b]pyran (4.00 g., prepared via cyclisation of 1-naphthyl propargyl ether in diethylaniline at 210°) was converted, via the same route as that described in Example 3, to 3,4-epoxy-3,4-dihydro-2H-naphtho[1,2-b]pyran (1.44 g.) m.p. 96°-99°. This epoxide (1.40g.) was treated with isopropylamine (1.00g., an excess) in refluxing ethanol (100 ml.) for 24 hours. Work-up as described in Example 4 yielded trans-4-isopropylamino-3,4-dihydro-2H-naphtho[1,2-b]pyran-3-ol D-(+)-hydrogen tartrate hydrate (0.30 g.) m.p. 108° - 110°.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]([O:19]C(=O)C)[CH2:16][C@@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][CH2:24][O-].[Na+].CCO>C(O)C>[CH2:23]([O:15][C:13](=[O:14])[C@H:12]1[CH2:16][C@H:17]([OH:19])[CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:24]
Reactant: CC(=O)O[C@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of N-CBZ-trans-4-acetoxy-D-proline (2.45 g, 7.31 mmol) in ethanol (50 mL) was added freshly prepared NaOEt/EtOH (0.017 g, 0.7 mmol of Na dissolved in 1 mL of EtOH). After stirring at room temperature for 20 minutes, the reaction was quenched with NH4Cl (0.1 g), and concentrated in vacuo to an oily solid. The desired alcohol was isolated (2.01 g, 94%) as a colorless oil by diluting the residue with ethyl ether (50 mL), filtering the solution through Celite, washing the filter cake with ethyl ether, and concentrating the combined filtrate and washings in vacuo. The alcohol was sufficiently pure to use directly in the next step: [α]25D +59° (c, 1.04 CHCl3); Spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-trans-4-hydroxy-L-proline ethyl ester; LRMS (CI, 70 eV, isobutane) m/e 294 (MH+, 100), 250 (98), 220 (24), 158 (25), 91 (89); HRMS (EI, 50 eV) m/e 293.1272 (293.1263 calcd for C15H19NO5).