Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice-water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 6.87 (dd, J=2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(F)cc1F
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)cc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,4-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.37 (s, 3H), 4.71 (d, J=5.6 Hz, 2H), 6.06 (bs, 1H), 6.47 (bs, 1H), 7.75 (t, J=9.4 Hz, 1H), 7.85 (t, J=10.0 Hz, 1H), 7.17 (t, J=7.3 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.12 (bs, 1H), 8.58 (d, J=2.8 Hz, 1H); MS (ESI) m/z 342.6 (M+1)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH2:25][CH3:26])=[C:18]3[N:23]([CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:25]([C:17]1[C:18]2[N:23]3[C:22]([CH:21]=[CH:20][CH:19]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:24]3[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:11][CH:12]=1)[CH3:26]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)cn2ccccc12
Product: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2c(C(=O)OC)c(C(=O)OC)c3cccc1n32

Procedure:
2-(4-(tert-Butyldimethylsilanyloxymethyl)phenyl)-1-ethylindolizine prepared in example 97, step 2, was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 4-ethyl-3-(4-(tert-butyldimethylsilanyloxymethyl)phenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate, which was hydrolysed and desilylated by the general synthetic principle outlined in example 23, step 7, to afford 4-ethyl-3-(4-hydroxymethylphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals in 63% yield. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.35 (t, 3H); 3.11 (q, 2H); 4.61 (d, 2H); 7.50 (d, 2H); 7.61 (d, 2H); 8.03 (dd, 1H); 8.32 (d, 1H); 8.42 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH:35][CH3:36]>C1COCC1.CCOC(C)=O>[CH3:34][N:35]([CH3:36])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C)c3)n2)n1
Yield: 54.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available dimethylamine (40% in water, 0.52 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 54%) as a white foam. MS (ISP) 498.3 [(M+H)+]; mp 155° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([N:10]1[C:14]([CH3:15])=[N:13][N:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]Br)[N:27]=1>CC#N>[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][O:1][N:2]=[C:3]([N:10]2[C:14]([CH3:15])=[N:13][N:12]=[N:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:27]=1
Reactant: Cc1nnnn1C(=NO)c1ccccc1
Reactant: BrCc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nnnn1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a stirred solution of N-hydroxy-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (2.0 g, 9.84 mmol, 1.0 eq.) in 50 ml of MeCN was added Cs2CO3 (3.52 g, 10.82 mmol, 1.2 eq.) followed by KI (0.163 g, 0.984 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-bromo-4-(bromomethyl)-1,3-thiazole (2.52 g, 9.84 mmol, 1 eq.) in one portion. The reaction was stirred for 24 hrs at room temperature. The solvent was evaporated then the residue was dissolved in EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (3.3 g, 88% yield) as a yellow viscous oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C[O:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])=O.S(=O)(=O)(O)O>O1CCCC1.O>[CH3:19][C:18]1[NH:17][CH:16]=[N:15][C:14]=1[C:12](=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: COC(=O)c1nc[nH]c1C
Reactant: Cc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)c1nc[nH]c1C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4.9 g of dry magnesium turnings are covered with 50 ml of dry tetrahydrofuran. The mixture is heated to boiling and a solution of 34 g of 2-bromotoluene in 50 ml of dry tetrahydrofuran is added dropwise at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for about 30 minutes until the magnesium turnings no longer react. The reaction mixture is then cooled to about 50° C. and 20 g of 5-methyl-4-imidazole-carboxylic acid methyl ester are added in small portions. After the addition is complete, the mixture is refluxed for another 2 hours and the solvent is then distilled off to give about half of the original volume. The mixture is cooled and poured into 300 ml of cold water containing 15 ml of concentrated sulfuric acid, with agitation. The stirring is continued for an additional 15 minutes and the mixture is then filtered. The pH of the filtrate is adjusted to 7-11 and the solution is extracted three times with 30 ml portions of chloroform. The combined chloroform extracts are washed with water and evaporated to dryness. The residue, which contains the crude product, is converted to the hydrochloride in ethanol. After recrystallization from ethanol, the hydrochloride melts at 289°-291° C. The 5-methyl-4-(2'-methylbenzoyl)-1H-imidazole is liberated from the hydrochloride in water with sodium hydroxide. It melts at 165°-166° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].O.[C:14](OCC)(=O)[CH3:15]>C1COCC1>[OH:2][CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:14][CH3:15]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(-c2cccs2)s1
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
5-Formyl-2,2'-bithiophene (3 g) was dissolved in THF (50 ml) and ethyl-magnesium bromide Grignard reagent (9.3 ml) was added dropwisely under nitrogen gas atmosphere in ice bath and stirred for 1 hour. The mixture was stirred for 1 hr. and then continuously stirred at room temperature. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (30 ml) and ethyl acetate (200 ml) were added to the mixture and extracted and purified by column chromatography, eluted with ethyl acetate/n-hexane (1/9). Light yellowish product was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=O)[N:4]2[C:22]([C:27]3C=[CH:31][CH:30]=[C:29](F)[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.C(N(CC)CC)C.Cl.[CH3:42][O:43][NH2:44]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][N:14]=2)[C:5](=[N:44][O:43][CH3:42])[N:4]2[C:22]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:23][C:24](=[O:25])[C:3]=12
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: CON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=c1c(Nc2ccncn2)cc(Cl)c2n1C1(CCCCC1)NC2=O
Temperature: 25 °C

Procedure:
To a solution of 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL) is added triethylamine (1.21 mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The reaction is stirred at reflux overnight. The resulting mixture is cooled to room temperature and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via flash column chromatography to afford 8′-chloro-5′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one (Cpd. No. 134).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>CN1CCCC1=O>[F:42][CH:43]1[CH2:46][N:45]([C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:9]=3)[N:12]=2)[CH2:44]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: FC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(N3CC(F)C3)c21
Temperature: 150 °C

Procedure:
150 mg (0.155 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (2.7 ml) in a reaction vessel suitable for a microwave, and 0.423 ml (2.430 mmol) of N,N-diisopropyl ethylamine and 270 mg (2.420 mmol) of 3-fluoroazetidine hydrochloride were added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 30 mg of the title compound was obtained (40% of theor.).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6]1)C.C[NH:29]N>CO>[CH3:1][N:2]1[CH:4]=[C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]2=[N:29]1
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reactant: CNN
Solvent: CO
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2

Procedure:
A solution of 0.150 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 44 μl of methylhydrazine in 5 ml of methyl alcohol is heated at reflux for 18 hours. A precipitate forms on standing. The volaties are evaporated to a residue which is purified by column chromatography on silica gel by elution with 5% ethyl acetate-methylene chloride. The product fractions are combined and the volatiles evaporated to a residue which is dissolved in chloroform-methanol, filtered through glass wool and the filtrate evaporated in vacuo to give 0.110 g of the desired product as pale yellow crystals.
Reaction SMILES: O1CCCC1.C([Li])CCC.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:54]=[CH:55][C:56]=1[O:57][CH2:58][C:59]1[N:60]=[C:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[O:62][C:63]=1[CH3:64])[CH2:29][N:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45](Cl)=[O:46])[C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.O>O1CCCC1>[CH3:64][C:63]1[O:62][C:61]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[N:60][C:59]=1[CH2:58][O:57][C:56]1[CH:55]=[CH:54][C:28]([CH2:29][N:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:45]([N:19]4[C@@H:18]([CH2:11][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:22][O:21][C:20]4=[O:23])=[O:46])[C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)Cl)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
9.1 mL of 2.44M n-butyllithium tetrahydrofuran solution was added thereto dropwise to tetrahydrofuran (30 mL) solution of 3.92 g of (S)-4-benzyl-2-oxazolidinone at −50° C. The mixture was stirred at −50° C. for 1 hour. Thereafter, the solution of the previously prepared (±)-{9-[3-methoxy-4-(5-methyl-2-phenyl-oxazole-4-ylmethoxy)-benzyl]-9H-carbazole-4-yloxy}phenylacetyl chloride in tetrahydrofuran (30 mL) was added thereto dropwise at −50° C. After the dropwise addition thereto, the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the prepared diastereomer mixture was purified by medium-pressure silica gel chromatography (ethyl acetate:n-hexane=5:1), and two types of the subject compound, 1.52 g of compound A (first fraction) and 1.2 g compound B (second fraction), were respectively prepared as pale brown powder.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[S:3]([O:6][C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32]C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:5])=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]([F:1])([F:45])[S:3]([O:6][C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:4])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.2 g, 0.304 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The mixture was stirred at rt for 1.5 h then was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (20 mL) and was extracted with dichloromethane (3×20 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated and adsorbed to silica gel then was purified by flash chromatography using a 12-100% ethyl acetate in hexanes gradient and a 12 g Thomson silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.109 g, 0.195 mmol, 64.3% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ=5.57 (dd, J=6.8, 1.9 Hz, 1H), 4.73 (d, J=1.6 Hz, 1H), 4.63-4.60 (m, 1H), 2.54 (td, J=10.9, 5.3 Hz, 1H), 2.17 (dd, J=17.1, 6.9 Hz, 1H), 2.08-1.99 (m, 1H), 1.70 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 1.82-0.91 (m, 20H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2CCCC2=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-oxopyrrolidin-1-yl)benzoic acid (19.94 mg, 0.097 mmol) in DCM (5 ml) was added oxalyl chloride (2M solution in DCM, 0.058 ml, 0.117 mmol) and 2 drops of DMF. The resulting mixture was stirred at r.t for 1 hr., then concentrated in vacuo. The residue (off white solid) was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[C:9]=1[C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:4])[CH3:3].[C:27]1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:9]1[C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:26])[CH3:25])=[CH2:27])[CH3:23]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OCC)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl (2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Intermediate 130, 1.4 g) in dry toluene (8 ml) dimethyl titanocene 9% w/w in toluene (Intermediate 131, 30 ml) was added and the reaction mixture was stirred for 1.5 hours at 90° C. After cooling the reaction was diluted with water (20 ml) and ethyl acetate (30 ml). Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents. This afforded the title compound as a yellow pale oil (865 mg).
Reaction SMILES: N#N.C[Si](C)(C)[S:5][Si](C)(C)C.C[O-].[Na+].[CH3:15][C:16]1([C:21]2[S:25][C:24]([CH2:26][C:27]#[N:28])=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1>CN(C=O)C.O>[CH3:15][C:16]1([C:21]2[S:25][C:24]([CH2:26][C:27]([NH2:28])=[S:5])=[CH:23][CH:22]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Reactant: CC1(c2ccc(CC#N)s2)OCCO1
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc(CC(N)=S)s2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethyldisilthiane (8.9 mL, 42.31 mmol) was added dropwise to a solution of NaOMe (2.35 g, 42.31 mmol) in dry DMF (35 mL) and the reaction mixture was stirred at rt for 15 min. This dark blue solution was then added to a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-acetonitrile (3.27 g, 16.93 mmol) in DMF (30 mL) and the reaction mixture was stirred for 2 days at rt. Water (100 mL) was then added and the mixture was extracted twice with EA (100 mL). The combined org. phases were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.35. LC-MS-conditions 02: tR=0.81 min, [M+H]+=244.38.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][Cl:3])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of thionyl chloride (47.6 g) in methylene chloride is slowly added to a solution of 4-(methylthio)benzyl alcohol (50.0 g) in pyridine (37.2 g) such that the temperature never exceeds 25° C. After the addition is complete the mixture is stirred an additional 2 hours at room temperature, then washed with water, dried, and the solvents removed. The resulting red oil is mixed with hexane which is decanted and evaporated to give 49.6 g of 4-(methylthio)benzyl chloride as a yellow oil, suitable for use in the reaction described next below.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.[C:17]1([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:17]1([C:23]2[N:24]=[N:25][N:26]([CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[CH2:4][CH2:3]3)[N:27]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: O=C(Oc1cccnc1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)N1CCC(n2nnc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of pyridin-3-yl 4-hydroxypiperidine-1-carboxylate (300 mg), 5-phenyl-1H-tetrazole (217 mg), triphenyl phosphine (460 mg), and THF (3 mL) was added dropwise a 2.2 M solution of diethyl azodicarboxylate in toluene (0.8 mL), followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 90/10), and purified again by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100). To the purified product was added hexane/ethyl acetate, followed by stirring, and then the resulting solid was collected by filtration and dried to obtain pyridin-3-yl 4-(5-phenyl-2H-tetrazol-2-yl)piperidine-1-carboxylate (250 mg) as a colorless solid.