Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH:12]C1C(C(F)(F)F)=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38]Cl.[H-].[Na+]>C1COCC1.C(Cl)(Cl)(Cl)Cl>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38][NH2:12]
Reactant: ClSc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: NSc1nc2ccccc2s1
Reaction time: 3 h

Procedure:
The sulfenylated diphenylamine was prepared from N-[2-chloro-5-(trifluoromethyl)phenyl]-2,4-dinitro-6-(trifluoromethyl)benzenamine (4.3 g, 0.010 mol) in dry THF (20 ml), 2-benzothiazolesulfenyl chloride [2.0 g, 0.010 mol, Zh. Obshch. Khim. 45, 1127 (1975)] in carbon tetrachloride (45 ml) and 50% NaH (0.53 g, 0.011 mol) as outlined in Example 1 with the following exception: the reaction mixture was stirred at 0° for 3 hours and then at room temperature for 16 hours. Purification by dry column chromatography (silica gel, hexane/ethyl acetate, 8.5/1.5) gave N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-trifluoromethyl)phenyl]-2-benzothiazolesulfenamide as a red-orange glass: mp 46°-53°; NMR (CDCl3) δ 7.20-8.25 (m, 7H, Ar-H), 8.8-9.05 (AB quartet, 1.6H, Ar-H); IR(KBr) 1600, 1540, 1500, 1330, 1270, 1170, 1150, 1130 and 1070 cm-1.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[C:19]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([OH:27])C>O>[OH:27][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:20]=[C:19]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[N:9]=1
Reactant: O=c1[nH]c2ccccc2c2cc(Cc3ccccc3)nn12
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2ccccc2c2cc(C(O)c3ccccc3)nn12
Reaction time: 0.5 h

Procedure:
1.65 g (0.0057 mole) of 2-benzylpyrazolo[1,5-c]quinazolin-5(6H)-one prepared as in part B above is stirred with 880 mg (4 equiv) of sodium borohydride in absolute ethanol (125 ml) at room temperature for 3 hours. The reaction mixture is stripped to dryness and the resulting solid is suspended in water (40 ml), cooled down to 0° and treated dropwise with 1 N HCl 25 ml). The mixture is stirred for 30 minutes, diluted with water (40 ml) and stirred for another 10 minutes. The white precipitates are filtered off, washed well with water and dried overnight in a vacuum over at 70° C. to give 1.6 g of product.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][NH2:18])[CH3:12].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([O:19][CH:14]([O:13][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][NH:18][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:21]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(CCCN)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
4-Formylbenzonitrile (612.0 mg) was dissolved in methanol (18.4 ml), and 4,4-diethoxybutylamine (752.5 mg) and trimethyl orthoformate (1.53 ml) were added thereto. The whole was stirred at room temperature for 18 hours. Subsequently, the solution was added with sodium borohydride (529.7 mg) under ice-cooling and stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.16 g) as a yellow oily substance.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:20]([CH2:21][CH3:22])=[CH:19][NH:18][N:17]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]([CH:2]([CH2:8][CH3:23])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:17]=1
Reactant: CCc1c[nH]nc1-c1ccccc1Cl
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCc1cn(C(CC)C(=O)N(C)C)nc1-c1ccccc1Cl

Procedure:
Using the procedure for Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(o-chlorophenyl)-4-ethylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained 3-(o-chlorophenyl)-α,4-diethyl-N,N-dimethylpyrazole-1-acetamide, m.p. 60°-63° C.
Reaction SMILES: CNC(=O)C1C=CC=C(C2C=CC(O[C@@H:17]3[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3)=C(C)C=2)C=1.Br[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=1.[CH3:40][O:41][C:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)=[O:43]>>[CH3:39][O:38][C:33]1[CH:32]=[C:31]([C:48]2[CH:49]=[C:44]([CH:45]=[CH:46][CH:47]=2)[C:42]([O:41][CH3:40])=[O:43])[CH:36]=[CH:35][C:34]=1[O:37][C@@H:17]1[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]1
Reactant: COc1cc(Br)ccc1O
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(OC)c2)c1
Yield: 3 %

Procedure:
4e was prepared using the same procedure as for 5b. In the first step of glycosidation reaction 4-bromo-2-methoxyphenol was used as glycosidation acceptor and in the second step of Suzuki coupling reaction 3-methoxycarbonylphenyl boronic acid was used instead. All intermediates were directly taken to the next step reaction without further purification. 4e was further purified by HPLC(C18, 15*150 mm column; eluent: acetonitrile/water (0.1% TFA)). Yield: 3%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 8.21 (t, J=1.51 Hz, 1H), 7.96 (td, J=1.44, 7.83 Hz, 1H), 7.84 (ddd, J=1.24, 1.92, 7.83 Hz, 1H), 7.49-7.61 (m, 1H), 7.30 (d, J=8.24 Hz, 1H), 7.24 (d, J=1.92 Hz, 1H), 7.13-7.21 (m, 1H), 5.47 (d, J=1.92 Hz, 1H), 4.11 (dd, J=1.79, 3.43 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.86-4.03 (m, 1H), 3.67-3.86 (m, 4H). MS (ESI): found [M+Na]+, 443.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH:1][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccc(C)cc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.836 g, 0.00152 mol) and p-toluenesulfonyl chloride (0.440 g, 0.00231 mol) in 40 mL of methylene chloride qas added 4 mL of pyridine. The reaction mixture was stirred for 54 h at room temperature, washed with 1N HCl, 1N NaOH solutions, dried over Na2SO4 and evaporated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 0.933 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH:26][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])(=[O:22])=[O:23])[CH2:16][CH2:15]1)([CH3:13])[CH3:12].[CH:11]([N:14]1[CH2:15][CH2:16][CH:17]([S+:21]=[CH:24][CH2:25][NH:26][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:18][CH2:19]1)([CH3:12])[CH3:13]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)cn2)CC1
Product: CC(C)N1CCC([S+]=CCNC(=O)c2ccc(Cl)cn2)CC1

Procedure:
5-Chloro-pyridine-2-carboxylic acid[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 9 starting from 104 mg (1.1 equiv.) 5-chloro-pyridine-2-carboxylic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-pyridine-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamo-yl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material. Yield: 60 mg MS (ES+): m/e=389, chloro pattern.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])([O-:22])=[O:21].[OH-].[Na+]>C(O)C>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)[CH3:19]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1

Procedure:
Ethyl 5-(4-ethoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(4-ethoxyphenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-ethoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[S:12][C:13]([Cl:17])=[CH:14][C:15]=1[NH-:16].C1(=O)N([O:23][C:24]([C:26]2[C:30]([C:31](O)=[O:32])=[CH:29][S:28][CH:27]=2)=O)C(=O)CC1.Cl>>[Cl:17][C:13]1[S:12][C:11]([Cl:10])=[C:15]2[C:14]=1[C:24](=[O:23])[C:26]1=[CH:27][S:28][CH:29]=[C:30]1[C:31](=[O:32])[NH:16]2
Reactant: O=C(O)c1cscc1C(=O)ON1C(=O)CCC1=O
Reactant: [NH-]c1cc(Cl)sc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Temperature: 0 °C
Yield: 94.2 %

Procedure:
109.5 g (116 ml; 1.50 moles) of dimethylformamide were added to 798 g (5.98 moles) of anhydrous aluminum chloride in the course of 15 minutes, while stirring, a highly exothermic reaction taking place. Thereafter, 250 g (0.596 mole) of thiophene-3,4-dicarboxylic acid succinimido ester [N-(2,5-dichlorothien-3-yl)]-amide were added to the stirred mixture at 80° C. in the course of 30 minutes. The reaction mixture was stirred for a further 3 hours at this temperature and then poured, in the warm state and while stirring, onto 4.5 kg of ice and 470 ml (561.2 g; 5.85 moles) of concentrated hydrochloric acid. The crystals precipitated during this procedure were filtered off under suction, washed in succession with 6 l of water, with twice 0.5 l of acetone and with twice 0.5 l of petroleum ether (boiling range 40°-60° C.) and dried at 50° C. in a drying oven under reduced pressure. 170.8 g (94%) of 1,3dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were isolated in the form of beige crystals of melting point 236.5°-239° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:16][C:15]=1[C:23]([F:24])([F:26])[F:25]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (109 μL; 1.28 mmol; 3 eq.), Intermediate 34 (120 mg; 0.43 mmol; 1 eq.), Intermediate 2 (94 mg; 0.43 mmol, 1 eq.) and DIEA (221 μL; 1.28 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11](C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)[CH2:10]1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[N:59]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:82]1([CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:80][NH:79][C:60]2[N:59]=[C:58]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:3]([NH:8][C@@H:9]4[CH2:13][CH2:12][NH:11][CH2:10]4)=[O:5])[CH2:10]3)[N:66]=[C:65]3[C:61]=2[N:62]=[CH:63][N:64]3[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with 1,3-di(R)-pyrrolidin-3-yl-urea (Intermediate B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH:28]=[CH2:27])=[CH:8][CH:7]=1
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OCC=C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 92.1 %

Procedure:
To a solution of 18 (30 g, 107.4 mmol, 1.0 equiv) in DMF (170 mL) at room temperature was added solid K2CO3 (29.6 g, 214.2 mmol, 2.0 equiv) then allylbromide (10.2 mL, 116.3 mmol, 1.1 equiv) dropwise. The suspension was stirred at room temperature for 9 hours, after which time water (500 mL) was added and extracted with ether (4×250 mL). The organics were combined, washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (20→60% EtOAc/hexane) afforded 19 (31.6 g, 92%) as a clear oil. Rf=0.27 (25% EtOAc/hexane); FTIR (neat, cm−1) 3343, 2919, 1721, 1510, 1239, 1215, 1176, 1052, 1017; 1H NMR (400 MHz, CDCl3) δ7.00 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.99 (m, 1H), 5.85 (m, 1H), 5.44 (d, J=8.0 Hz, 1H), 5.36 (dd, J=17.4, 1.2 Hz, 1H), 5.25 (s, 1H), 5.22 (dd, J=10.2, 1.6 Hz, 1H), 5.15 (dd, J=10.4, 1.2 Hz, 1H), 4.56 (dd, J=14.2, 6.0 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.45 (d, J=5.2 Hz, 2H), 3.66 (s, 3H), 3.03 (dd, J=14.4, 5.2 Hz, 1H), 2.96 (dd, J=14.0, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ172.0, 157.5, 155.4, 133.1, 132.5, 130.0, 127.8, 117.4, 117.3, 114.5, 68.4, 65.5, 54.7, 52.0, 37.0; MS (ES+) calculated for C17H21NO5 (M+H)+: 320.1420, found: 320.2.
Reaction SMILES: [CH3:1][O:2][P:3]([O-:6])[O:4][CH3:5].C(N(CC)CC)C.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C.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>[CH3:1][O:2][P:3]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([C:14](=[O:16])[CH3:15])[N:18]=[CH:19]2)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: CC(=O)n1ncc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COP(=O)(OC)c1ccc2c(cnn2C(C)=O)c1
Temperature: 105 °C
Yield: 55.2 %

Procedure:
291 μl (1.09 eq; 3.172 mmol) of dimethylphosphite, 442 μl (1.09 eq; 3.172 mmol) of triethylamine and 134 mg (0.04 eq; 0.116 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 897 mg (1 eq; 2.91 mmol) of trifluoromethanesulfonic acid 1-acetyl-1H-indazol-5-yl ester in solution in 60 ml of dimethylformamide. The medium is heated at 105° C. for 4 hours under an argon atmosphere. The solvent is evaporated off under reduced pressure in a rotary evaporator, with 40 ml of toluene being added. The reaction crude is taken up in 40 ml of ethyl acetate and then washed with 50 ml of water. The organic phase is dried over magnesium sulfate and then filtered and the solvent is evaporated off under reduced pressure in a rotary evaporator. 973.6 mg of crude product are obtained. The reaction crude is purified by flash chromatography (silica 35-70 μm), eluent: ethyl acetate/cyclohexane 80:20 to obtain 430.5 mg of (1-acetyl-1H-indazol-5-yl)phosphonic acid dimethyl ester.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:16][C:17]([CH2:20][Si](C)(C)C)=[C:18]=[CH2:19])[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:20]=[C:17]1[C:18](=[CH2:19])[C:11]23[O:15][CH:7]([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12]3)[CH2:16]1
Reactant: C=C=C(CC(O)CCC1CCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=C1CC2CCC3CCCC3(O2)C1=C
Temperature: -78 °C

Procedure:
1.50 mL of diethyl ether was added to 2-(3-hydroxy-5-trimethylsilanylmethyl-hepta-5,6-dienyl)-cyclopentanone (98 mg, 0.35 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (63 μL, 0.35 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane={fraction (1/15)}) to obtain 60 mg of the pro duct (91%).
Reaction SMILES: O1CCCCC1O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14].C([O:17][CH2:18][CH3:19])C.[CH:20]1[CH:25]=CC=C[CH:21]=1>>[OH:17][CH2:18][CH2:19][CH2:21][CH2:20][CH2:25][CH2:8][C:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]=1
Reactant: O=CCCCCCOC1CCCCO1
Reactant: CCOCC
Reactant: c1ccccc1
Product: O=C1CCC=C1CCCCCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 6-(2-tetrahydropyranyloxy)hexanal (23.2 g., 0.116 mole) and 1-morphdinocyclopentene (25.5 g., 0.16 mole) in benzene (30 ml.) was heated under reflux for 12 hours under nitrogen, and the water liberated was continuously removed with a Dean and Stark head. Benzene (12 ml.) and then, dropwise, 18% hydrochloric acid (28 ml.) were added and the mixture was stirred for 2 hours. The organic layer was separated and evaporated. Concentrated hydrochloric acid (84 ml.) and butanol (350 ml.) were added to the residue. The mixture was heated at 100°C. for 1 hour, and then the solution was concentrated to give an oil. Diethyl ether was added, and the ether solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 2-(6-hydroxyhexyl)-2-cyclopenten-1-one (10.7 g., 50%), b.p. 105°-160°C./15 mm.Hg, nD25 1.491.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[N:14]=[C:13]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:16])[CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH2:16])[N:14]=1
Reactant: CC(O)(c1ccccc1)c1cccc(Br)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccccc1)c1cccc(Br)n1
Temperature: 5 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
At 0° C. triethylsilane (1.09 g, 9.4 mmol, 1.3 equiv) was added to compound 7 (2.0 g, 7.2 mmol, 1.0 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (4.1 g, 36.1 mmol, 5.0 equiv) was added dropwise while maintaining the temperature<5° C. The reaction was allowed to warm to room temperature at which point the solution became a yellowish-green color. The reaction was stirred for 96 hr, LC/MS and TLC indicated the reaction was incomplete. The reaction was then refluxed for an additional 18 hr, at this point LC/MS and TLC indicated the reaction was complete. The reaction was carefully quenched with saturated sodium bicarbonate (100 mL). The layers were separated, the organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (30 g) by eluting with heptanes (150 mL), ethyl acetate (2%) in heptanes (200 mL) and ethyl acetate (5%) in heptanes (200 mL). The desired product was isolated pure in nearly 70% yield (1.3 g).
Reaction SMILES: CC1S[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[OH:9][CH2:7][C@H:5]1[N:6]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:11][C@@H:10]2[C@H:4]1[CH2:15]2
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CO
Temperature: 25 °C

Procedure:
To a solution of racemic 7-1 (7.2 g, 63.6 mmol, synthesized as in Example 1) in dichloromethane (320 mL) at 0° C. was added diisopropylethylamine (10.7 g, 83.0 mmol) followed by CbzCl (11.9 g, 70.0 mmol) and the reaction mixture was slowly warmed to ambient temperature over 48 h. The mixture was then quenched with water and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to an oil. The oil was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the product as an oil. ESI+ MS: [M+H]+ 248.3.