Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]([CH:9]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH3:25])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:26](O)=[O:27])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:17]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[CH3:25])[C:26](=[O:27])[C:4]=2[CH:3]=1
Reactant: CCn1c(Br)cc(C(=O)O)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
A solution of 5-bromo-2-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-ethyl-1H-pyrrole-3-carboxylic acid (Step K1) (3.11 mmol), TBTU (4.36 mmol) and DIEA (9.33 mmol) was stirred at 80° C. for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layers were washed successively with H2O and brine, dried (MgSO4), filtered and concentrated. The product was purified by chromatography column to afford the title compound as a colorless oil. tR: 5.90 min (HPLC 4); ESI-MS: tR=1.35 min, [M+H]+ not ionized (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 100 °C

Procedure:
D5 (100 mg) was dissolved in DMF (1.5 ml). To this solution was added K2CO3 (58 mg) followed by ethyl 3-bromopropionate (72 ul) and the mixture stirred and heated to 100° C. After 1 hour only 5% conversion was observed by LCMS so further portions of K2CO3 (97 mg) and ethyl 3-bromopropionate (72 ul) were added. After 3 hours the reaction mixture was evaporated then partitioned between DCM and H2O. The aqueous layer was extracted with DCM then the combined DCM solutions were washed with brine, dried over MgSO4, filtered and evaporated to give the crude product. This was purified on a silica cartridge, eluting with a 0 to 50% mixture of Et2O in petroleum ether. This gave the title compound (40 mg) as a white solid. δH (CDCl3, 400 MHz): 1.21 (3H, t), 1.45 (6H, d), 2.85 (2H, t), 4.13 (2H, q), 4.51 (2H, t), 4.71 (1H, septet), 6.60 (1H, d), 7.07 (1H, d), 7.21 (1H, d), 7.45 (1H, d), 8.02 (1H, d), 8.08 (1H, d), 8.27 (1H, s), 8.47 (1H, s). MS (ES): C24H24ClN3O4 requires 453; found 454 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Br:25])=[O:6].[Cl:30][C:31]1[N:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[Cl:30][C:31]1[N:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:9]([Br:25])=[CH:10][C:11]([C:15]([F:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:12][C:13]=2[Br:14])[C:3]=1[F:29])=[O:34]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1F
Product: O=C(Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1F)c1cccnc1Cl

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 3-amino-N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-2-fluorobenzamide and 2-chloronicotinic acid chloride.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=[C:18]([F:21])[C:19]=1F.[H-].[Na+]>C1COCC1>[CH:1]1([C:4]2[N:8]([C:19]3[C:18]([F:21])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=3[F:13])[N:7]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 25 °C

Procedure:
Intermediate 5 (1 g, 5.7 mmol) and 3,4,5-trifluoronitrobenzene (1 g 5.7 mmol) were dissolved in THF and added sodium hydride (274 mg, 11.3 mmol). Mixture was refluxed for 2 h and reaction mixture cooled to rt and quenched with water. Work-up (H2O/AcOEt) gave the desired product as a yellow gummy liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.05-8.01 (m, 2H), 6.31 (s, 1H), 1.60-1.50 (m, 1H), 1.00-0.91 (m, 2H), 0.80-0.71 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[C:18]([Cl:20])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.[OH-].[Li+]>O>[Cl:20][C:18]1[C:17]([S:21]([CH2:23][CH3:24])=[O:22])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)CC)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)c1cc2[nH]c(-n3cc(C(=O)O)cn3)nc2cc1Cl
Temperature: 23 °C
Reaction time: 56 h
Yield: 85.5 %

Procedure:
To a solution of 1-(5-chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (100 mg, 0.273 mmol), THF (1.0 mL), and water (0.33 mL) was added lithium hydroxide (31.3 mg, 0.818 mmol). The mixture was sonicated briefly, and stirred at 23° C. for 56 h. The solvent was evaporated, water was added, and the resulting solution was acidified to pH 1 with 1M aq. HCl. The precipitate was collected to yield the titled compound (79.1 mg, 85% yield). MS (ESI/CI): mass calcd. for C13H11ClN4O3S, 338.0; m/z found, 339.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13.88 (br s, 1H), 13.01 (br s, 1H), 8.94 (s, 1H), 8.40 (s, 1H), 8.03-7.55 (m, 2H), 3.23-3.11 (m, 1H), 2.89-2.78 (m, 1H), 1.08 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:24])[C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:24][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:25]
Reactant: CN1C(=O)N(C2CCN(Cc3ccccc3)CC2)Cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)N(C2CCNCC2)Cc2ccccc21
Yield: 63.7 %

Procedure:
2 g palladium charcoal was added to 7.3 g 3-(1-benzyl-piperidin-4-yl)-1-methyl-3,4-dihydro-1H-quinazolin-2-one in 150 mL methanol and stirred for 5 h under 50 psi hydrogen atmosphere. The mixture was filtered and the solvent was removed. Diethylether was added and the precipate was filtered to yield 3.4 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][NH:40][CH3:41])[N:30]=2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][N:40]([CH3:41])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:14][CH:13]=3)[N:30]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CNCCn1nc(-c2cccc(Br)c2)c2cnccc21
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(CCn1nc(-c2cccc(Br)c2)c2cnccc21)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and {2-[3-(3-bromo-phenyl)-pyrazolo[4,3-c]pyridin-1-yl]-ethyl}-methyl-amine (Table No. 1, SM 6) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=616.
Reaction SMILES: F[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[N:27][NH:28][CH:29]=1)=[O:24]>C(#N)C.CS(C)=O>[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:29]=1)=[O:24]
Reactant: CNC(=O)c1cn[nH]c1
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CC#N
Solvent: CS(C)=O
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
PCT application WO 2012/149196 describes preparation of polymorph D by a relatively complicated procedure. First, a “cross coupling” reaction of 2-fluoroadenosine with N-methylpyrazol-4-carboxamide in an acetonitrile/dimethylsulfoxide mixture provides crude 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, which is then purified by reverse-phase chromatography using a methanol/water mixture. After concentrating at 150° C. under reduced pressure, polymorph D is obtained as a white solid substance containing variable amounts of water.
Reaction SMILES: [CH2:1]=[C:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[ClH:23].Cl.[NH2:25][CH2:26][CH2:27][O:28][NH2:29]>>[ClH:23].[NH2:25][CH2:26][CH2:27][O:28][N:29]=[C:17]1[CH2:16][CH2:15][C@@:14]2([CH3:21])[CH:19]([C:2](=[CH2:1])[CH2:3][C@@H:4]3[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]3[CH2:6][CH2:7][C:8]2=[O:22])[CH2:18]1
Reactant: NCCON
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Agent: Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=NOCCN)CC12
Yield: 40 %

Procedure:
Prepared in 40% yield as described in Example 1 starting from 6-methyleneandrostane-3,17-dione (II-ah, Prepn. 8) and 2-aminoethoxyamine dihydrochloride. The crude product (1.65 g) was crystallized twice from EtOAc to give the title compound I-ai. H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.97 (bb, 3H), 4.81 (bs, 1H), 4.49 (bs, 1H), 4.08 (t, 2H), 3.10 (m, 1H), 3.02 (t, 2H), 2.45-0.85 (m, 19H), 0.77 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[C:13](Br)[CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH2:3][CH2:2]1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH2:3][CH2:2]1
Reactant: Brc1cc(CC2CC2)cc2cccnc12
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cc(CC3CC3)cc3cccnc23)cc1

Procedure:
6-(cyclopropylmethyl)-8-bromoquinoline and benzene boronic acid can be combined to form 6-(cyclopropylmethyl)-8-phenylquinoline,
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:35])([F:34])[C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[N:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:27]([C:24]2[N:25]=[N:26][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]4[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=4[C:10]([F:35])([F:34])[F:9])[CH2:20][CH2:19]3)=[CH:22][CH:23]=2)=[O:28])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: Nc1ccc(Cl)nn1
Product: O=C(Nc1ccc(Cl)nn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 24, making variations only as required to use 3-amino-6-chloropyridazine in place of 2,2-(dimethylcyclopropyl)methylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (8% yield). 1H NMR (300 MHz, CDCl3) δ 10.75, 8.62, 8.06, 7.75-7.50, 7.36, 7.03, 4.12-3.76, 3.36. C NMR (75 MHz, CDCl3) δ 167.7, 162.2, 160.1, 154.0, 152.3, 143.8, 134.1, 132.4, 129.7, 129.6, 127.3, 127.2, 126.94, 126.88, 126.7, 120.7, 112.2, 46.3, 44.6, 44.3, 41.3. MS (ES+) m/z 492.1 (M+1).
Reaction SMILES: [CH:1](O)=[CH:2][CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Br:42])CCCCCCCCCCCCCCCCC>>[Br:42][CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17][CH:16]=[CH:15][CH2:14][CH:13]=[CH:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]=[CH:6][CH2:5][CH:4]=[CH:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCC=CC=CC=CC=CC=CC=CO
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCCBr
Yield: 92 %

Procedure:
From docosahexaenyl alcohol 1e (201 mg, 0.64 mmol), using the procedure described above for preparation of 1-bromooctadecane (2a), (all-Z)-1-bromo-4,7,10,13,16,19-docosahexaene (2e) (221 mg, 92%) was obtained as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH2:15][NH2:16])[OH:14].[BH4-].[Na+]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:16][CH2:15][CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CNCCO)cc1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example S3-C using 4-tert-butylbenzaldehyde (1000 mg, 6.17 mmol), ethanolamine (371 μl, 6.17 mmol) and sodium borohydride (350 mg, 9.25 mmol). The desired product (1190 mg, 93%) was isolated without further purification as a colourless oil. MS (ISP) 208.3 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].[N+:8]([CH3:11])([O-:10])=[O:9]>>[N+:8]([CH2:11][CH2:1][CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6])([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)CCC
Product: CCCC(=O)CCC[N+](=O)[O-]

Procedure:
To 53.4 g (544 mmol) of 1-hexen-3-one in 250 mL of methanol and 294 mL (5440 mmol) of nitromethane was added as a slow, steady stream 30 mL (136 mmol) of 25% NaOMe in methanol. The resultant yellow solution was warmed to −5° C. over 1 h, and kept between −5° C. and −10° C. for an additional 3 h. The solution was warmed to 0° C. for 1 h and was then quenched with 250 mL of saturated NH4Cl. The mixture was diluted with 200 mL brine to aid in layer separation, and extracted with ether (2×250 mL). The combined ether extracts were washed with Brine, dried with MgSO4, filtered and concentrated to give 75.7 g (88%) of a yellow liquid. 1H NMR revealed the presence of ca. 10% of 7-nitro-trideca-4,10-dione arising from the combination of one molar equivallent of nitromethane with two molar equivallents of 1-hexen-3-one. The products are insepararable by silica gel chromatography (EtOAc/hexanes), so the material was generally used in the next step without purification. Title compound: mass spectrum m/e=144 (M−1).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C@@H:10]2[CH2:12][O:11]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(O)C.C([N:18]([CH2:21][CH3:22])CC)C>>[N:18]1([CH2:12][C@H:10]([OH:11])[CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1nccn1C[C@@H]1CO1
Reactant: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C[C@@H](O)CN1CC1

Procedure:
A solution of 0.3 g (1.8 mole) of (R)-(+)-2-nitro-1-(2-oxiranylmethyl)-1H-imidazole, 0.24 g (5.4 mmole) of 1H-aziridine, and 3.5 mL of 99:1 absolute ethanol:triethylamine is heated at reflux for 10 minutes, cooled, and concentrated. The residue is crystallized from 99:1 absolute ethanol:triethylamine to give 0.22 g of product, mp 118.5°-120° C. [α]D24 =+23.5° [C0.98, chloroform].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19])=[O:4].[H-].[Na+].[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1Cc2ccc(C(=O)OC)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)Cc2ccc(C(=O)OC)cc2C1=O
Temperature: 60 °C
Yield: 80.1 %

Procedure:
To a stirred solution of 3-oxo-indan-2,5-dicarboxylic acid 2-ethyl ester-5-methyl ester (Step 1, 500 mg, 1.9 mmol) in dry DMF (0.7 ml) was added sodium hydride (84 mg, 2.0 mmol, 60% in mineral oil) and then heated at 60° C. for 1 h. Then ethyl bromo acetate (350 mg, 2.0 mmol) was dissolved in dry DMF (1.4 ml) and added to the reaction mixture at room temperature and then again heated at 60° C. for 3 h. After completion of the reaction mixture was concentrated and H2O (5 ml) was added. The suspension was extracted with ethyl acetate and combined organic layer was washed with brine, dried and concentrated. The crude was purified by column chromatography using 20% ethyl acetate-hexane to give the desired compound (530 mg). 1H NMR (400 MHz, CDCl3) d 8.42 (1H, s), 8.30 (1H, d), 7.57 (1H, d), 4.37 (4H, m), 3.92 (3H, s), 3.90 (1H, d), 3.28 (2H, m), 2.90 (1H, d), 1.15 (3H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C.[Pd]>[NH2:22][C:21]1[C:2]([CH3:1])=[C:3]([CH:18]=[CH:19][CH:20]=1)[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Cc1c(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
A solution of t-butyl (2S)-2-[(2-methyl-3-nitrophenoxy)methyl]pyrrolidine-1-carboxylate (7.63 g, 21.9 mmol) and 10% Pd/C (0.38 g) in ethanol is hydrogenated (50 psi) at room temperature for 4 h and filtered. The filtrate is concentrated in vacuo to afford the title compound as an off-white solid, 6.66 g, mp 110° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([CH2:10][N+:11]([O-])=O)[CH2:6]2)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][CH2:10][C:7]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][CH:5]2[CH:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC1=CC2C(C1)CC2(CN)CC(=O)O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
Tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N solution of hydrochloric acid in ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 1 Step (b) (10 g) was dissolved in DMF (50 ml) and triethylamine (14.8 ml) was added. tert-Butyl 3-bromopropylcarbamate (10 g) was then added and the solution stirred at room temperature for 24 hrs. The solvent was evaporated and the resulting solid dissolved in ethyl acetate and water were added, the organic phase separated, dried, filtered and evaporated to a solid (17.51 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]#[C:7][C:8]2([CH3:22])[CH2:13][CH2:12][C:11]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]=3[O:9]2)[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]2[O:9][C:8]([C:7]#[C:6][C:4]3[C:3]4[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=4[S:1][CH:5]=3)([CH3:22])[CH2:13][CH2:12][C:11]=2[C:14]=1[CH3:21])(=[O:29])[CH3:28]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1csc3ccccc13)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#Cc1csc3ccccc13)O2

Procedure:
A mixture of 0.3 g of rac-2-[(benzo[b]thiophen-3-yl)ethynyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 20 ml of pyridine and 1 ml of acetic anhydride was allowed to sit at room temperature over night and was then evaporated to dryness under reduced pressure. The residue was crystallized from hexane to yield 0.25 g of colorless crystals with m.p. 99°-101°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:25][CH:24]3[CH:19]([N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][CH2:23]3)[CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][CH2:23][CH:24]2[CH2:25][N:17]([C:4]3[C:5]4[CH2:12][CH2:11][CH2:10][C:9]5[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=5[C:6]=4[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:18][CH:19]12
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c(c(N3CC4CCCNC4C3)n1)CCCc1ccccc1-2
Reaction time: 2 h

Procedure:
A solution of Example 59D in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL), stirred for 2 hours, concentrated and partitioned between 1M NaOH solution and CH2Cl2. The organic layer was isolated, dried over MgSO4 and concentrated to yield the title product. 1H NMR (CDCl3) δ 0.86 (m, 1H), 1.77 (m, 5H), 2.16 (m, 2H), 2.30 (m, 1H), 2.64 (m, 3H), 3.03 (m, 1H), 3.43 (m, 3H), 3.87 (m, 2H), 4.73 (bs, 2H), 7.19 (m, 1H), 7.33, (m, 2H), 7.75 (m, 1H). MS (M+H)+ m/z 336.