Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:12]([NH2:21])[CH:11]=2)=[CH:4][N:3]=1.[N:22]1([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH:26]=[N:25][CH:24]=[N:23]1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]3[N:16]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:29]([C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[N:21][C:12]=3[CH:11]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccccc1-n1cncn1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)c(CO)c2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-n2cncn2)nc2cc(-c3cnc(N)c(CO)c3)ccc21
Reaction time: 4 h
Yield: 10.4 %

Procedure:
To a solution of [2-amino-5-(3-amino-4-tert-butylamino-phenyl)-pyridin-3-yl]-methanol (100 mg, 0.35 mmol) in DMF (5 mL) is added 2-[1,2,4]-triazol-1-yl-benzaldehyde (73 mg, 0.42 mmol) at room temperature. Oxone (215 mg, 0.35 mmol) in H2O (1 mL) is added and the solution is stirred for 4 hours. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (16 mg, 10%) as a pale brown foam. LCMS (ESMS): m/z 440.20 (M++1)
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:44][C:45]1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nnc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as white solid. MS(m/e): 371.2 (MH+).
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:32])[C:26]=3[N:25]([C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:32])[C:26]=3[N:25]([C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncc(F)c21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution of [5-(benzhydrylidene-amino)-pyridin-3-yl]-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 36, 1 g, 1.65 mmol) in THF (80 mL), citric acid (30 mL, 1 M) was added at room temperature and stirred for 4 hours, then quenched with saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic phase was dried over sodium sulphate, evaporated in vacuo to afford the crude compound, purified by column chromatography over alumina (gradient of DCM: Methanol 98:2 to 97:3) to afford the title compound as a pale yellow solid (69%, 500 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].[Br:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(OCC)(=O)C>C(Cl)Cl.O>[CH2:19]=[CH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([O:20][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][Br:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCCCCCCC(O)CCCCCCCC=C
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C=CCCCCCCCC(CCCCCCCC=C)OC(=O)CCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a solution of the alcohol 11 (5.6 g, 20 mol) in anhydrous DCM (300 mL) was added slowly and carefully Bromobutryl chloride (20 mmol) at 0° C. under inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 20 h and monitored by TLC (silica gel, 10% ethyl acetate in hexanes). Upon completion of the reaction, mixture was diluted with water (400 mL) and organic layer was separated out. Organic phase was then washed with sat. solution of NaHCO3 (1×400 mL) followed by brine (1×100 mL) and concentrated under vacuum. Crude product was then purified by silica gel (100-200 mesh) column, eluted with 2-3% ethyl acetate in hexane solution to give 6 g (90%) of desired product 12 as colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 2H), 5.05-4.81 (m, 5H), 3.46 (t, J=6.5 Hz, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.17 (p, J=6.8 Hz, 2H), 2.11-1.93 (m, 4H), 1.65-1.44 (m, 4H), 1.43-1.17 (m, 19H). 13C NMR (101 MHz, cdcl3) δ 172.51, 139.37, 114.35, 77.54, 77.23, 76.91, 74.86, 34.31, 33.99, 33.01, 32.96, 29.65, 29.56, 29.24, 29.09, 28.11, 25.52.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: CC(=O)c1ccc(N)cc1
Product: CC(=O)c1ccc(NC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1574 g, 0.53 mmol) and 4′-aminoacetophenone (0.0876 g, 0.65 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 412 (M+H)+; (ESI−) m/z 410 (M−H)−; 1H NMR (300 MHz, CD3OD) δ 2.63 (s, 3H), 7.51 (dd, J=8.1, 4.7 Hz, 1H), 8.07 (dd, J=8.1, 1.4 Hz, 1H), 8.11 (s, 4H), 8.19 (dd, J=8.0, 1.5 Hz, 1H), 8.30 (dd, 1H), 8.45 (d, J=8.1 Hz, 1H), 8.65 (dd, J=4.7, 1.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Yield: 62 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-4-methylbenzoic acid (400 mg) and 3-(trifluoromethyl)aniline were converted to the title compound (410 mg, 62%)
Reaction SMILES: IC1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)C(C)(C)C.Cl[CH2:16][CH2:17][CH2:18][C:19]#[CH:20].O.C(OCC)(=O)C>C(N(CC)CC)C.[Pd](Cl)Cl.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.[Cu]I>[CH2:17]1[C:18]2=[CH:19][C:20]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]2[CH2:9][CH2:16]1
Reactant: C#CCCCCl
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1cc2cc3n(c2cn1)CCC3
Yield: 56.7 %

Procedure:
A mixture of 0.2885 g bis(triphenylphosphine) palladium dichloride and 0.1565 g copper (I) iodide in 200 mL triethylamine was heated to reflux for 20 min. To the resulting solution was added at room temperature 25.00 g N-(4-iodo-3-pyridinyl)-2,2-dimethyl-propanamide and 25.3 g 5-chloro-1-pentyne and the mixture was heated to reflux for 30 min. The reaction mixture was distributed between water and ethyl acetate, the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was taken up in 200 mL tert-butanol and 18.45 g powdered potassium hydroxyde was added. The mixture was heated to reflux for 30 min. The reaction mixture was distributed between water and ethyl acetate, the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with ethyl acetate:methanol=7:3 to yield 7.37 g 2,3-Dihydro-1H-3a,5-diaza-cyclopenta[a]indene as slightly yellow solid melting at 90-91° C.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=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][CH2:14][CH2:15][CH3:16].O[CH2:30][CH:31]([OH:33])[CH3:32].B(F)(F)F.CCOCC>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([O:26][CH2:30][CH:31]([OH:33])[CH3:32])=[O:25])=[CH:27][CH:28]=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][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC(C)O)cc1

Procedure:
The title ester is prepared as in Example 23 by the reaction of 4-(hexadecylamino)hydrocinnamic acid with 1,2-dihydroxypropane and boron trifluoride etherate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:4](=[O:6])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Nc1ccccn1
Reactant: COC(=O)c1cccc(C(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)Nc2ccccn2)c1N
Yield: 65.1 %

Procedure:
A solution of 2-amino-3-(methoxycarbonyl)benzoic acid 20 (1 g, 5.1 mmol), 2-aminopyridine 21 (723 mg, 7.7 mmol), HOBT (1.39 g, 10.3 mmol), EDCI (1.9 g, 10.3 mmol) and DMAP (1.25 g, 10.3 mmol) in DMF (40 mL) was stirred at 70° for 12 h. The reaction mixture was poured into H2O. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 22 (0.9 g, 58% yield).
Reaction SMILES: CO[C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH3:21])[C:14]([C:4]1[C:3](=[O:24])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([F:13])[CH:9]=2)[NH:6][CH:5]=1)=[O:23]
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cc1C
Temperature: 25 °C
Yield: 66.1 %

Procedure:
0.691 g (2.11 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(4-fluoro-phenylamino)-acrylic acid methyl ester 2g was dissolved in 30 mL of diphenyl ether and the resultant solution was heated at 250° C. After 2.5 h the solution was cooled to room temperature and diluted with 50 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was further washed with hexane to yield 0.412 g of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 3j as a brown solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](P(=O)(OCC)OCC)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH-].[Li+].CCOCC>O1CCCC1.O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1/[CH:10]=[CH:9]/[P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C/P(=O)(OCC)OCC
Yield: 80.1 %

Procedure:
Tetraethyl[2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (2.0 g, 3.61 mmol) prepared according to Example 9 was dissolved in tetrahydrofuran (26 ml). Lithium hydroxide (0.152 g, 3.62 mmol) was dissolved in water (10 ml) and added to the tetrahydrofuran solution. After stirring the reaction overnight, ether was added, and the aqueous phase was extracted with ether. The combined ether layers were dried (MgSO4) and stripped down. The residue was chromatographed on silica eluting with 3% ethanol in hexane. Tlc on silica, developed in 5% ethanol in hexane, was used to identify product, Rf =0.04. Impure fractions were combined and rechromatographed as necessary to give 1.21 g, 2.89 mmol, 80% yield of the product as a pale yellow liquid; 1H NMR (CDCl3) ∂ 0.88 (m, 3H), 1.15 to 1.81 (several m, 24H), 2.46 (t, J=7.1 Hz), 4.15 (m, 4H), 6.37 (t, J=18 Hz, 1H), 7.26 (m, 2H), 7.42 (m, 1H), 7.54 (m, 1H), 7.95 (dd, J=23.0, 17.7 Hz, 1H); EI mass spectrum m/z 419 (M+H)+.
Reaction SMILES: COC(=O)[C@@H](N(C(OCC1C=CC=CC=1)=O)CC=O)C.N[C@H](CO)CCC(N1CCC2(CC2)[C@H](O)C1)=O.[CH2:38]([O:45][C:46]([N:48]1[C@@H:53]([CH3:54])[C:52](=[O:55])[N:51]2[C@@H:56]([CH2:59][CH2:60][C:61]([N:63]3[CH2:70][CH2:69][C:66]4([CH2:68][CH2:67]4)[C@H:65]([OH:71])[CH2:64]3)=[O:62])[CH2:57][O:58][C@H:50]2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]([N:48]1[C@@H:53]([CH3:54])[C:52](=[O:55])[N:51]2[C@@H:56]([CH2:59][CH2:60][C:61]([N:63]3[CH2:70][CH2:69][C:66]4([CH2:67][CH2:68]4)[C@H:65]([OH:71])[CH2:64]3)=[O:62])[CH2:57][O:58][C@@H:50]2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C[C@H]1C(=O)N2[C@@H](CCC(=O)N3CCC4(CC4)[C@H](O)C3)CO[C@H]2CN1C(=O)OCc1ccccc1
Agent: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: N[C@H](CO)CCC(=O)N1CCC2(CC2)[C@H](O)C1
Product: C[C@H]1C(=O)N2[C@@H](CCC(=O)N3CCC4(CC4)[C@H](O)C3)CO[C@@H]2CN1C(=O)OCc1ccccc1

Procedure:
Condensation of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 1) with (S)-4-amino-5-hydroxy-1-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-pentan-1-one in analogy with examples 1/2F produced a nearly statistical mixture of the title compound [light brown gum, MS: 472.4 (M+H)+], and its epimer, (3S,6S,8aS)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3-oxo-propyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester [light brown gum, MS: 472.4 (M+H)|], which were separated by column chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)N2CCOCC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][N+:11]([O-])=O)=[CH:5][C:4]=1[O:14][CH3:15].[Li+].[BH4-].Cl[Si](C)(C)C>C1COCC1>[CH3:15][O:14][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][NH2:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
Using the same procedure and workup as described in Example 15, 1,2-dimethoxy-4-(2-nitro-vinyl)-benzene (I-40a: 4 g, 19.13 mmol) in dry THF (66 mL) was reacted with LiBH4 (1.6 g, 76.55 mmol) and chloro trimethyl silane (19.3 mL, 152.6 mmol) at 0° C., The resulting mixture was stirred at room temperature for 72 hours to afford 3.46 g of the product (100% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[C:19]2[CH3:26].Cl>C(O)(C)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[OH:14])[N:5]=[CH:4][CH:3]=[C:2]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[C:19]2[CH3:26])#[N:13]
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Agent: Cl
Solvent: CC(C)O
Product: Cc1[nH]c2ccc(Nc3ccnc4cc(O)c(C#N)cc34)cc2c1C
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A solution of 4-chloro-6-cyano-7-hydroxyquinoline (852 mg, 4.2 mmol), (prepared as described for the starting material in Example 1), and 5-amino-2,3-dimethylindole (800 mg, 5 mmol) in isopropanol (25 ml) containing 6.2N HCl in isopropanol was heated at 80° C. for 2 hours. After cooling, the solid was collected by filtration, washed with isopropanol followed by ether and dried under vacuum. The solid was partitioned between acetonitrile/ethyl acetate (1/1) and water. The pH of the aqueous layer was adjusted to 7–8 with saturated aqueous sodium hydrogen carbonate followed by 1N citric acid. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated to give 6-cyano-4-(2,3-dimethylindol-5-ylamino)-7-hydroxyquinoline (650 mg, 47%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:14])=O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C(=O)O)cc1
Product: CCc1ccc(C(=O)Cl)cc1

Procedure:
200 g (1.33 millimoles) of 4-ethylbenzoic acid are added rapidly to 500 ml of thionyl chloride with stirring. The mixture is heated at the reflux temperature for 4 hours. After evaporation of the SOCl2 and distillation, 4-ethylbenzoyl chloride is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1>C(O)C>[CH3:14][O:13]/[N:15]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CO/N=C1\CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 5-bromoindanone (6.03 g) in 40 mL ethanol was added 3.58 g methoxylamine hydrochloride and 3.5 mL pyridine. The mixture was stirred at ambient temperature for 1 hour and heated at 80° C. for 3 hours. The volatiles were removed under vacuum and the solid residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to yield 6.74 g (98% yield) of a tan solid. 1H NMR (CDCl3) was consistent with an isomeric mixture of the desired structure, with the E oxime isomer as the major component. LC/MS indicated 2 close peaks, both with a M+1 molecular ion of m/z 242.0 by positive ESI.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-methyl-4-(trifluoromethyl)phenylcarbamate (1 1.6 g, 42 mmol) was dissolved in trifluoroacetic acid (17% in dichloromethane, 90 mL) and stirred at room temperature for 30 min. The reaction was concentrated and taken up in water/pentane. The aqueous was neutralized with saturated sodium bicarbonate, and the layers separated. The organics were dried over magnesium sulfate and concentrated to give 7.8 g (quant.). 1H-NMR (CDCl3, 500 MHz) δ 7.25-7.40 (m, 2H), 6.67 (d, J=7.9 Hz, 1H), 3.87 (bs, 2H), 2.18 (s, 3H); 13C-NMR (CDCl3, 126 MHz) δ 147.7, 127.5 (q, J=3.8 Hz), 125.0 (q, J=271 Hz), 124.4 (q, J=3.8 Hz), 120.3 (q, J=33 Hz), 114.1, 17.2. Mass spec.: 176.03 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cc(F)ccc5n4)cc3CC[C@@H]12
Yield: 62.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-fluoro-quinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 96 mg (62%) of the title compound as a solid. mp 152°-155°. FDMS: m/e=406. α[D]589 =+63.16 (c=0.61, chloroform).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([O:22]CC)=[O:21])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([OH:22])=[O:21])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCn1nnc(C(=O)OCC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCn1nnc(C(=O)O)n1
Reaction time: 28 h

Procedure:
To a room temperature, stirred solution of potassium hydroxide (1.97 g, 0.035 mol) in absolute ethanol (280 mL) was added in one portion 2-dodecyl-2H-tetrazole-5-carboxylic acid, ethyl ester (8.7 g, 0.028 mol), and the mixture was stirred for 28 hours. A white precipitate formed. The solids were filtered off, washed with ethanol, and partitioned between ethyl acetate and 10% hydrochloric acid. The organic layer was washed with saturated sodium chloride, dried (MgSO4), and rotoevaporated to a white solid, yield 7.74 g (98%), mp=122°-124° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][CH2:13][C:9]2([CH2:12][O:11][CH2:10]2)[CH2:8][CH2:7]1>CO.[OH-].[OH-].[Pd+2]>[CH2:10]1[C:9]2([CH2:13][CH2:14][NH:6][CH2:7][CH2:8]2)[CH2:12][O:11]1
Reactant: COc1ccc(CN2CCC3(CC2)COC3)c(OC)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CC2(CCN1)COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 7-(2,4-Dimethoxy-benzyl)-2-oxa-7-aza-spiro[3.5]nonane (125) (300 mg, 1.1 mmol) in MeOH (10 mL) was added Pd(OH)2 (300 mg). The reaction solution was stirred at RT overnight under H2 atmosphere. LCMS showed that most of the staring material was consumed. The mixture was filtered and concentrated to give the product (126) (112 mg, 0.88 mmol, yield: 80%). ESI-MS (M+1): 128 calc. for C7H13NO 127.