Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:21]=1)(C(OCC)=O)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+].O1CCCC1>O1CCCC1>[C:22]([C:20]1[CH:21]=[C:17]([CH2:16][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][OH:7])[S:18][CH:19]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC#Cc1csc(CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(CC(CO)NC(C)=O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
To a solution of diethyl (acetamido)[[4-(1-dodecynyl)-2-thienyl]-methyl ]propanedioate (12.3 g) in dry tetrahydrofuran (100 ml) was added 2M lithium borohydride/tetrahydrofuran (12.8 ml), and the mixture was stirred at 60° C. for 4 hrs. The solution was cooled, quenched with a 50:50:10 solution of methanol:water:acetic acid, and extracted with ethyl acetate. The organic extracts were evaporated, and the residue was chromatographed on silica gel (9:1 ethyl acetate:dichloromethane). The appropriate fractions were collected and evaporated. The residue was crystallized from ether:heptane to give 5.3 g (57%) of product, mp 55°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[CH:16])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:21]=1[NH2:22]>C(N)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:21]1[CH:23]=[CH:24][C:25]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:26][C:20]=1[F:19]
Reactant: Nc1ccc(I)cc1F
Reactant: C#CCCN1CCC(Cc2ccc(Cl)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1ccc(C#CCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1F
Yield: 17.6 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-1-(but-3-yn-1-yl)piperidine (400 mg, 1.53 mmol) and 2-fluoro-4-iodoaniline (436 mg, 1.84 mmol) in 10 mL of butylamine is added 70 mg of Pd(PPh3)4. The resulting solution is allowed to reflux for 24 hr. The solvent is evaporated in vacuo and the residue is purified by flash chromatography giving the title product as a brown oil (100 mg, 18%): 1H NMR (CDCl3) 1.25 (m, 2 H), 1.46 (m, 1 H), 1.58 (m, 2 H), 1.97 (m, 2 H), 2.56 (m, 6 H), 2.88 (m, 2 H), 3.83 (bs, 2 H), 6.62 (m, 1 H), 6.80-7.24 (m, 6 H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[N:4]=1.[CH3:10][OH:11]>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:11][CH3:10])[N:4]=1
Reactant: Brc1cccc(Br)n1
Reactant: CO
Agent: [Na]
Product: COc1cccc(Br)n1

Procedure:
Dried sodium (970 mg, 42.2 mmol) was added portionwise to cooled methanol (50 ml) under nitrogen, and once addition was complete, 2,6-dibromopyridine (10 g, 42.2 mmol) was added portionwise. The resulting suspension was heated under reflux for 24 hours. The cooled reaction was concentrated under reduced pressure, the residue diluted with water (100 ml), and extracted with ethyl acetate (2×75 ml). The organic extracts were dried (MgSO4), and evaporated under reduced pressure to give a pale yellow oil. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 98:2) to give the title compound as a clear oil, 4.23 g.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([CH2:3][OH:29])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C=CCc1c(O)ccc2c(=O)c3c(F)cccc3oc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c2ccc3c(c2oc2cccc(F)c12)CC(CO)O3
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A mixture of 4-allyl-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (1.4 g), m-chloroperbenzoic acid (1.2 g) and chloroform (250 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. After addition of potassium carbonate (2 g) and water (50 ml), the mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 1.2 g of 7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene. m.p. 220°-221° C. This compound gave a mass spectrum having a molecular ion peak at m/e 286.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]2[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)=[CH:6][CH:5]=1>CO.O>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]2[C:15]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Sodium hydroxide (52.0 mg, 1.30 mmol) was added to a solution of methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (140 mg, 0.32 mmol) in methanol (30 mL) and water (1.0 mL). The reaction was stirred overnight at room temperature and then concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][SH:21].CC(C)([O-])C.[K+]>O1CCCC1>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([S:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:22])[CH:12]=[C:6]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: Cc1ccccc1CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1CSc1cc2n(c(=O)n1)CCCN2C
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a suspension of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (200 mg, 1.002 mmol) and o-tolylmethanethiol (166 mg, 1.202 mmol) in tetrahydrofuran (THF) (5 mL) stirred in air at room temperature was added potassium tert-butoxide (112 mg, 1.002 mmol) in one charge. The reaction mixture was stirred at rt for 3 hr. The resulting mixture was concentrated and purified by prep-HPLC to give 50 mg 1-methyl-8-((2-methylbenzyl)thio)-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (50 mg, 0.158 mmol, 15.73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COCCNC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 51.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 151 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 5-amino-2-[4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl) amino]piperidin-1-yl]benzonitrile (0.9 g), the title compound (0.6 g) was obtained, melting point: 194° C.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][O-:11].[Na+]>CO.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:2][O:11][CH3:10])=[CH2:9])[CH3:8]
Reactant: C[O-]
Reactant: C=C(CBr)C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(COC)C(=O)OCC
Temperature: 0 °C
Yield: 28.7 %

Procedure:
A solution of ethyl α-(bromomethyl)acrylate (0.99 g, 5.1 mmol [Villieras J., Rambaud M., Synthesis, 1982:924–926]) in methanol (10 mL) is added to an ice-cold solution of sodium methoxide (0.33 g, 6.1 mmol) in methanol (50 mL). The suspension is refluxed for 21 hours, cooled, diluted with water and extracted with dichloromethane. The organic extracts are dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound (0.211 g). 1H NMR (200 MHz, CDCl3): δ 6.33–6.26 (m, 1H), 5.88–5.80 (m, 1H), 4.23 (q, 2H), 4.19–4.10 (m, 2H), 3.41 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C(Cl)C1CCCCC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCCCC1
Yield: 72.4 %

Procedure:
Using the general method of Example 92, cyclohexanecarbonyl chloride (94 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide as a white powder, m.p. 188-190° C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30; Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (EI) calcd for C22H30N6O (M+) 394.2481 found 394.2475.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47])C.[Cl:49]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:49][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:45])[C@@H:5]1[C@H:46]([OH:48])[CH3:47]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2ccccc2)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3ccccc3)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of 2.75 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(phenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 25 ml of dry chloroform at -40° C. was added a solution of 5.3 mmol of chlorine in 7 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound (1.98 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1.Cl>CN(C=O)C.O>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]2=[O:18])=[CH:27][CH:26]=1
Reactant: ClCc1ccncc1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1ccncc1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles) and potassium carbonate (346 mg, 2.5 mmoles) in 20 ml DMF was added solid 4-picolyl chloride.HCl (164 mg, 1.0 mmole) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 100 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 84 mg (48% yield) of the desired 6-(4-pyridylmethyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 170.5°-172.5° C.; TLC in 1:1 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ5.20 (s, 2H), 7.15 (dd, 2H, J=4.7, 1.5), 7.28-7.50 (m, 6H), 8.52 (dd, 2H, J=4.4, 1.5), 8.69 (dd, 1H, J=8.1, 2.1), 8.90 (dd, 1H, J=4.7, 1.8); 13C NMR (75 MHz, CDCl3) δ161.86, 154.58, 151.75, 150.46, 144.94, 136.83, 136.59, 134.20, 134.01, 130.01, 129.58, 128.23, 127.98, 122.37, 122.32, 121.93, 120.47, 51.25; IR (KBr) vmax 3435, 3051, 1668, 1630, 1591,1552, 1483, 1415, 1367, 1358, 1342, 1292, 1097, 997, 827, 794, 729, 702, 601, 472 cm-1 ; mass spectrum (EI), m/e 347. Anal. (C 20 H14ClN3O.3/8) Calcd.: C, 67.75; H, 4.19; N, 11.85; Cl, 9.99. Found: C, 67.95; H, 4.09; N, 11.84; Cl, 9.99.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
52 mg (E)-ethyl 2-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (8a) was dissolved in 2 ml THF, to which was added 2 ml aqueous solution containing 107 mg Na2S2O4. The resulting biphasic solution was stirred at r.t. for 1 h until it turned pale yellow. The mixture was diluted with ethyl acetate and washed with water and brine. Dried over Na2SO4, the organic solution was filtered and the filtrate was concentrated. The crude product was purified via flash column (EtOAc/Hexane) yielding 25.2 mg (58.7%) title compound, m.p.: 116-118° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5].[C:13]([C:16]([CH2:23][Br:24])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(O)=[O:14].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:24][CH2:23][C:16]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[C:13]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=[O:5])=[O:14]
Reactant: NCC(=O)c1cccc(Br)c1
Reactant: CCOC(CBr)(OCC)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(CBr)(OCC)C(=O)NCC(=O)c1cccc(Br)c1
Reaction time: 18 h

Procedure:
The 2-amino-1-(3-bromophenyl)ethanone hydrochloride (4.6 g, 19 mmol), HO2CC(OEt)2CH2Br (5.0 g, 21 mmol), and NMM (12.5 mL, 113 mmol) were suspended in anhyd THF (270 mL) under N2 and PyBOP (10.8 g, 21 mmol) was added in one portion. The reaction mixture was stirred for 18 h and concentrated to ¼ vol and the precipitates were removed by filtration (HCl salt of NMM). The mother liquor was taken up in dichloromethane and washed with water. After concentration, the crude residue was subjected to flash chromatography (silica gel) eluting with 60% EtOAc/hexanes to give Intermediate J.1, 5.3 g (65%). 1H NMR (500 MHz, DMSO-d6): δ 8.27 (t, J=5.5 Hz, 1H), 8.14 (t, J=1.5 Hz, 1H), 8.00 (dt, J=7.9, 1.2 Hz, 1H), 7.87 (dd, J=8.8, 1.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 3.67 (s, 2H) 3.58-3.46 (m, 4H), 1.18 (t, J=7.0 Hz, 6H). LCMS: 2.2 min; LRMS: Calcd. for C15H19Br2NO4: 435.98. Found: 435.98 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:22])[CH2:4][CH2:5][C:6]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]=1[C:14]1[C:9](=[CH:10][C:11]([O:16]C)=[CH:12][CH:13]=1)[CH2:8][CH2:7]2.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:22])[CH2:4][CH2:5][C:6]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]=1[C:14]1[C:9](=[CH:10][C:11]([OH:16])=[CH:12][CH:13]=1)[CH2:8][CH2:7]2
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(O)cc1CC2

Procedure:
A solution of 4-bromo-10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone (18 mg, 0.05 mmol) in anhydrous CH2Cl2 (0.5 mL) was cooled in an ice bath, stirred, and treated with 1M BBr3 in CH2Cl2 (0.3 mL, 0.3 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 175 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% CH3OH in CH2Cl2. The UV visible product band was eluted with 10% CH3OH in CH2Cl2 and the eluant was evaporated under vacuum to provide 4-bromo-10a-butyl-7-hydroxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as an oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2].[CH3:11][SiH:12]([CH3:14])[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-]>CCCCC>[CH2:1]([C:3]([Si:12]([CH3:14])([CH3:11])[Cl:13])([CH2:9][CH3:10])[CH:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2]
Reactant: CCC(CC)=C(CC)CC
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CCC(CC)C(CC)(CC)[Si](C)(C)Cl
Reaction time: 2 h

Procedure:
2.1 g of tetraethylethylene, 2 ml (18 mmol) of dimethylchlorosilane and 200 mg of AlCl3 are reacted according to Example 1. After 2 hours, the reaction mixture is diluted with pentane and the precipitate is filtered off. The pentane is stripped from the filtrate in vacuo and the residue is distilled. This gives 2.8 g (80 % of theory) of product as a colourless liquid. Boiling point= 75° -80° .C/0.195 mbar.
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.2 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.816 g, 7.033 mmol) in t-butyl methyl ether (16 ml), lithium hydroxide monohydrate (0.271 g, 6.46 mmol) was added and the mixture was stirred for 2.25 hours at room temperature. A solution of methyl (Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (8) (1.554 g, 3.920 mmol) in t-butyl methyl ether (4.7 ml) and water (0.75 ml) were added thereto, and the mixed solution was heat refluxed for approximately 24 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 47 g, ethyl acetate:hexane=1:4), to give methyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (9) (1.787 g; 3.380 mmol; yield: 86.2%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C=O)C>[CH2:22]([C:8]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:23]
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
A solution of 1C (10 g, 38.16 mmol) in DMF (60 mL) was added over a period of 30 min to an ice cold solution of NaH (2.29 g, 95.41 mmol) in DMF (40 mL), and the mixture was stirred for 10 min. Ethyl iodide (17.86 g, 114.48 mmol) was then added, and the mixture was stirred for 2 h at room temperature. The reaction was then brought to 0° C., excess NaH was quenched with ice water and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (7.0 g, 64%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J=9.0 Hz, 1H), 6.82 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 6.6 (d, J=2.1 Hz, 1H), 4.1 (q, J=7.2 Hz, 2H), 3.8 (s, 3H), 3.12-2.9 (m, 3H), 2.47 (d, J=15.9 Hz, 1H), 2.42 (m, 1H), 2.03 (dt, J1=13.5 Hz, J2=4.5 Hz, 1H), 1.8-1.6 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.9 (t, J=7.5 Hz, 3H). ESI-MS m/z=291 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:23])[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:23])[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](OC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](OC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])c1ccccc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, (1S)-1-phenylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-hydroxy-3,3-dimethylbutanoate (35b) (0.30 g, 0.76 mmol) dissolved in 6 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 99 mg (1.53 mmol) of sodium azide (NaN3). After work-up, the crude material (35c) was used in the next step without further purification. MS (ESI) m/z 422.05 (M+Na)+.