Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[I:17][CH2:18][CH2:19][CH2:20]O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:17][CH2:18][CH2:19][CH2:20][O:3][C:2](=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1
Reactant: OCCCI
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1NC2CSC(CCCCC(=O)OCCCI)C2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
A solution of biotin (125 mg, 0.5 mmol), 3-iodo-1-propanol (150 μL, 1.6 mmol) and TsOH (10 mg, 0.05 mmol) in PhMe (50 mL)) was heated under reflux and Ar for 3 d in a Dean-Stark apparatus. After cooling down to ambient temperature, the mixture was filtered and the solvent distilled off under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed with H2O (5 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to yield 4 (75 mg, 36%) as a white solid. FABMS: m/z=413 [M+H]+; 1H-NMR (400 MHz, CDCl3): δ=1.40-1.45 (2H, m), 1.61-1.75 (4H, m), 2.10-2.16 (2H, m), 2.30 (2H, t, 7 Hz), 2.79 (1H, d, 13 Hz), 2.88 (1H, dd, 5 and 13 Hz), 3.15-3.18 (1H, m), 3.22 (2H, t, 7 Hz), 4.13 (2H, t, 6 Hz), 4.42-4.45 (1H, m), 4.61-4.65 (1H, m), 7.22 (1H, d, 8 Hz); 7.72 (1H, d, 8 Hz); 13C-NMR (100 MHz, CDCl3): δ=25.0, 28.4, 28.8, 32.6, 34.2, 40.5, 55.8, 61.8, 63.6, 64.4, 164.5, 173.9.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:14][CH2:15][N:16]([CH2:30][CH2:29][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:18]3)[NH:10][C:9]2=[O:19])=[CH:20][CH:21]=1
Reactant: O=C1NC2(CCNCC2)C(=O)N1Cc1ccc(Br)cc1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC2(CCN(CCC(c3ccccc3)c3ccccc3)CC2)C(=O)N1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 32.1 %

Procedure:
A mixture of 26.2 mg (70 μmol) of 3-(4-bromo-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride, 21.4 mg (70 μmol) of 3,3-diphenylpropyl bromide and 29 mg (210 μmol) of potassium carbonate in 1 mL of anhydrous DMF was heated overnight at 60° C. After cooling to room temperature, 0.5 mL of water was added and the solution was extracted with DCM (2×2 mL). The crude material was purified by semi-preparative HPLC (method A) yielding 12.8 mg (32.1%) of Compound 3 as a white solid.
Reaction SMILES: C(OC(N1CCC2C(=CC=C(C(=O)C[Br:20])C=2)C1)=O)(C)(C)C.[OH:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)[CH3:24]>>[Br:20][CH2:32][C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:23]([OH:22])[CH3:24])=[CH:26][CH:27]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)CBr)ccc2C1
Reactant: CC(=O)c1ccc(C(C)O)cc1
Product: CC(O)c1ccc(C(=O)CBr)cc1

Procedure:
2-Bromo-1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone is prepared following preparation 29c from 600 mg (3.65 mmol) 1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(=O)(=O)(O)O.[CH3:19]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]c2ccccc12

Procedure:
Indole-3-acetic acid (25 g, 143 mmol) was dissolved in 500 mL of methanol and 5 mL of concentrated sulfuric acid was added. The resulting solution was heated under reflux overnight. TLC analysis indicated the absence of starting material and the reaction mixture was concentrated in vacuo. The residue was dissolved in 300 mL of ethyl ether, washed with 5% aqueous sodium bicarbonate (2×150 mL), dried over magnesium sulfate, filtered and concentrated to 24.09 g (89.1%) of the ester as a burgandy colored oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])[N:7]=1)=[O:5])C.[CH3:32][NH2:33]>CO.C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])[N:7]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 86 %

Procedure:
A solution of 150 mg (0.324 mmol) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 0.8 ml of methanol is treated with 0.40 ml (3.24 mmol) of a ˜8M methylamine solution in ethanol. The mixture is stirred for 22 hours at room temperature and then concentrated in vacuo. The crude product is taken up in water and the pH of the solution is adjusted to 3 with 1 M aqueous HCl solution and the mixture is stirred for 3 hours at 0° C. The crystals are filtered, washed with cold water and dried in vacuo to give 124 mg (86%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid methylamide as white crystals, m.p. 257-260° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[C:14]1[CH:20]=[C:19](O)C=[CH:17][C:15]=1O>CO>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:17][CH2:15][CH2:14][CH2:20][CH3:19]
Reactant: Cc1cc(O)ccc1O
Reactant: CCC=CCCCCCCCC
Solvent: CO
Product: C=CCCCCCCCCCCCCCCC
Reaction time: 17 h

Procedure:
8-methoxycarboniltetracyclo[4.4.0.12,5.117,10 ]-3-dodecen of 65 grams, dicyclopentadien of 87 grams and methylhydroquinon of 0.14 gram were mixed in a 300 milli-litter eggplant type flask, and the reaction was continued at 170 degrees to 180 degrees in centigrade for 17 hours. The reaction product remained cooled, and residual 8-methoxycarboniltetracyclo[4.4.0.12,5.117,10 ]-3-dodecen and residual dicyclopentadien were distillated in vacuum. Hot methanol was added to the residue, and insoluble content was filtrated. The filtrate was concentrated in vacuum, and residue was recrystallized from methanol. Then, we obtained white crystal of 12-methoxycarbonilhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 10 grams.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[NH:9]1)=[O:7])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:42])([CH3:43])[CH2:33][O:34][CH3:45])[NH:9][CH:8]2[C:6]([OH:5])=[O:7])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 82 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.0 g, 1.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.9 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:23]([C:11]2[C:2]([OH:1])=[CH:3][C:4]3[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=3[CH:10]=2)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and benzoyl chloride (155 mg, 1.10 mmol) followed by stirring at 60° C. for 1 hour. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 27.3 mg (9%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:15]#[N:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
16.8 g (0.08 mole) (3RS)-1-benzyl-3-chloromethyl pyrrolidine and 5.88 g (0.12 mole) of sodium cyanide was dissolved in 250 ml dimethyl sulfoxide. The mixture was stirred at 60° C. for two days and at room temperature for one week. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 14.7 g (92%) of the product.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1>>[O:16]([C:2]1[CH2:6][CH2:5][O:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1cccc(O)c1
Product: c1ccc(OC2=NOCC2)cc1

Procedure:
3-phenoxy-4,5-dihydroisoxazole I-176a and I-176b were prepared in 2 steps from racemic compound I-14. Bromo-4,5-dihydroisoxazole I-14 was reacted with 3-hydroxybenzoic acid methyl ester using Method 5 followed by hydroysis using the analogous conditions as in example 94. [M+H]+=368.0 m/z. Activity: C
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])#[N:2].CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([N:14]([CH2:13][CH:8]1[C:9]2[C:4](=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:35]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCC1CCCc2c(C#N)cccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCCc2c(C#N)cccc21)C(=O)CCl
Reaction time: 8 h

Procedure:
A solution of tert-Butyl (2-{[(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (0.20 g, 0.61 mmol) in DCM (5 mL) was added Et3N (74 mg, 7.2 mmol), followed by chloro-acetyl chloride (81 mg, 7.2 mmol). The reaction mixture was stirred overnight. The product was purified by prep-TLC (Pet Ether:EtOAc=1:1) to give the title product. MS m/z: 406 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6](=[CH2:25])[CH2:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:13]1)=[O:11])=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:6](=[CH2:25])[CH2:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[NH:13]1)=[O:11])([OH:5])=[O:3]
Reactant: C=C(CCCC(=O)N1CCC[C@@H](C(=O)OC(C)(C)C)N1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(CCCC(=O)N1CCC[C@@H](C(=O)OC(C)(C)C)N1)C(=O)O
Yield: 47.9 %

Procedure:
A solution of 8.2 g of tert.butyl 1-[5-(ethoxycarbonyl)-5-hexenoyl]-hexahydro-3-(S)-pyridazinecarboxylate in 25 ml of ethanol was treated with 23.7 ml of 1N aqueous sodium hydroxide solution for 16 hours. The solution was diluted with 80 ml of water and the volume was then reduced to 80 ml by evaporation. The solution was washed with diethyl ether and the pH of the aqueous solution was adjusted to 3 using 2N aqueous hydrochloric acid. The solution was then extracted with dichloromethane. The organic solution was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution, whereby there were obtained 3.62 g of tert.butyl 1-[5-(carboxy)-5-hexenoyl]-hexahydro-3(S)-pyridazinecarboxylate in the form of a white solid of melting point 86°-88° C., from n-hexane.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:8]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])[NH:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:8]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])[NH:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Yield: 79.9 %

Procedure:
After N-benzyloxycarbonyl-L-leucyl-L-argininal dibutylacetal hydrochloride (0.92 g, 1.60 mmol) was dissolved in methanol (100 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.56 g (80%) of L-leucyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]=[O:16])[CH3:5])[O:2]1.[I-].[CH3:32][S+](C)C.CC([O-])(C)C.[K+]>CN(C)C=O.ClCCl>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]2[CH2:32][O:16]2)[CH3:5])[O:12]1
Reactant: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C=O)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C5CO5)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Temperature: 0 °C

Procedure:
3.8 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-5α-androstane-15α-carbaldehyde in 46 ml of dimethylformamide is stirred under argon with 3.0 g of trimethylsulfonium iodide and 2.3 g of potassium tert-butylate at room temperature. After 30 minutes the reaction mixture is added to ice/water. The precipitated product is suctioned off, dissolved in dichloromethane, washed neutral with water. 3.5 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-15α-(2-oxiranyl)5α-androstane is obtained as foam.
Reaction SMILES: C([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7][C@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])(=O)C.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]1[CH:35]1[CH2:40][CH2:39][N:38]([C:41](OC2C=CC([N+]([O-])=O)=CC=2)=[O:42])[CH2:37][CH2:36]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]1[CH:35]1[CH2:36][CH2:37][N:38]([C:41]([O:16][C@H:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C@@H:5]([OH:4])[C@H:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7][CH2:8]2)=[O:42])[CH2:39][CH2:40]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CC(=O)O[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 1 h

Procedure:
In an oven-dried 100 mL round-bottom flask was suspended (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate (96.7 mg, 0.290 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (167 mg, 0.435 mmol) in dimethylformamide (3 mL) under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (0.870 mL, 0.870 mmol) was added dropwise. The resulting dark-red solution was stirred under nitrogen at −15° C.˜0° C. for 1 h. LCMS showed desired product and possible over-hydrolysed product. After another 1 h at room temperature, complete hydrolysis was not yet achieved. The reaction was quenched with sodium bicarbonate solution and volatiles were removed. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the acetate-protected product (2nd peak, 51 mg, 30%, not pure) as well as the target alcohol (3rd peak, 20 mg, 13%). In a 250 mL round-bottom flask was (5S,6S,9R)-5-acetoxy-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (51 mg, 0.088 mmol) (acetate protected product from above) in methanol (1 mL) to give a colorless solution. Potassium carbonate (122 mg, 0.883 mmol) was added, and the mixture was stirred at room temperature for 1 h. LCMS indicated complete conversion. Methanol was removed in vacuo. The residue was partitioned between water and ethyl acetate. The layers were separated (no product in aqueous layer by LCMS). The organic layer was washed with brine, dried, and concentrated to give a white solid. Purification by FCC up to 10% methanol/methylene chloride afforded the desire product (28 mg, 56%) as a light yellow solid. 1H and 19F NMR spectra were obtained and matched that of example 4.
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][CH:7]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[C:23]([CH3:36])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:37])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50](Br)[CH:49]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[C:50]([C:24]2[CH:25]=[CH:26][C:21]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:42])[CH3:43])[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:11]([CH3:37])[CH:12]=3)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=2[CH3:36])[CH:51]=[CH:52][CH:53]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 49.3 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 24-(1); 70 mg, 0.116 mmol), (3-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 53 mg, 0.232 mmol), tetrakis(triphenylphosphine)palladium (0) (26.8 mg, 0.023 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1) to give the title compound (36 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C@@:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:27])([CH3:26])[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C@@:13]4([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:14]4)[C:10]4([CH2:11][CH2:12]4)[C:9]([CH3:27])([CH3:26])[O:8][C:5]3=[CH:6][CH:7]=2)=[O:37])=[N:34][CH:35]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a mixture of tert-butyl [(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (100 mg, 0.268 mmol), 5-methoxypyrazine-2-carboxylic acid (45 mg, 0.30 mmol) and 1H-benzotriazol-1-ol (40 mg, 0.29 mmol) in dichloromethane (2 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 hours and directly purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:1) to afford tert-butyl [(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (108 mg).