Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)(O)[O-].[Na+].C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][C:12]=1[O:22][CH3:23])(=O)C.Cl>CO>[CH3:23][O:22][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[OH:10])[C:18](=[O:21])[CH2:17][CH2:16][CH2:15]2
Reactant: COc1cc2c(cc1OC(C)=O)C(=O)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.9 %

Procedure:
3.5 mL of water and then 3.5 mL of saturated aqueous sodium bicarbonate was added to 117 mg of 7-acetoxy-6-methoxytetralin- 1-one dissolved in 7 mL of methanol. The resulting solution was stirred under nitrogen at 25° C. for 17 hours. Thereafter the solution was acidified with aqueous hydrogen chloride and extracted five times with 6 mL portions of methylene chloride. The combined methylene chloride extracts were washed once with brine and dried over anhydrous magnesium sulfate. The dried extract was separated by filtration and the methylene chloride was removed from the filtrate by evaporation at reduced atmospheric pressure and gave 94 mg of 6-methoxy-7-hydroxytetralin-1-one having m.p. 151-152° C.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]([NH2:25])=[S:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>C(O)C.O1CCOCC1>[S:24]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:25]=[C:23]1[NH:22][C:12]1[CH:13]=[CH:14][C:15]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:10]([O:9][CH3:8])[CH:11]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1CCCC1Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 40 mg (0.33 mmol) 2-chlorocyclopentanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1.5 ml) and dioxane (1.5 ml). The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 41 mg (42%) (5,6-dihydro-4H-cyclopentathiazol-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 327.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.25 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.01 (s, 1H), 3.78 (s, 3H), 2.78 (br t, 2H), 2.67 (br t, 2H), 2.35 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1>[Cu]>[Cl:17][C:16]1[C:11]([S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:12][CH:13]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:15]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCCCCCCCS
Agent: [Cu]
Product: CCCCCCCCSc1ncc(C(F)(F)F)cc1Cl
Temperature: 185 °C
Reaction time: 4 h

Procedure:
At 23° C., 17.6 g (0.1166 mol) of n-octanethiol were added with stirring over a period of 5 minutes to a mixture of 25 g (0.1132 mol) of 97.8% pure 2,3-dichloro-5-trifluoromethylpyridine and 7 mg (0.1 mol %) of copper powder, and the mixture was stirred at 185° C. for 4 h. After cooling, the reaction mixture was partitioned between methylene chloride and water and the organic phase was dried and concentrated. 35.4 g (96.1% of theory) of the title compound of 24 n D
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([O-:12])=[O:11])=O)(C)(C)C>Cl>[NH2:8][C@H:9]([C@@H:13]([OH:18])[C:14]([CH3:16])([CH3:15])[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)[O-])[C@@H](O)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[C@H](O)[C@@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, the diastereomeric mixture containing (2R*,3R*)- and (2R*,3S*)-2-(tert-butoxy-carbonylamino)-3-hydroxy-4,4-dimethyl-pentanoate (0.4 g, 1.38 mmol) was dissolved in a 6.0 M HCl solution (30 mL). The resulting solution was divided into two equal aliquots and stirred at 130° C. for 1 h. All portions were joined and the reaction mixture extracted with Et2O (3×20 mL). The aqueous phase was concentrated under reduced pressure giving a yellowish solid crude product, as a diastereoisomeric mixture (anti:syn=9:1), which was used without further purification in the following step. MS (ESI) m/z: 162 [M−H]+; (ESI) m/z: 160 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:13]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]1=2>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:18]([C:17]2[S:13][C:14]3[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=3[CH:16]=2)(=[O:20])=[O:19])=[C:5]([NH:10][S:18]([C:17]2[S:13][C:14]3[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=3[CH:16]=2)(=[O:19])=[O:20])[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 53.3 %

Procedure:
N,N′-(4-Trifluoromethyl-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (100 mg) was prepared by using 4-trifluoromethyl-benzene-1,2-diamine (0.06 g, 0.33 mmol) and benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following procedure as in Example 32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([F:39])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:10]2[N:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:4]=3)[N:9]=2)=[C:26]([F:39])[CH:25]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1
Reactant: CC1(C)OB(c2ccc(Cl)cc2F)OC1(C)C
Product: Fc1cc(Cl)ccc1-c1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1

Procedure:
A solution of 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine and 2-(4-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled together by the method of Example 2 to give 3-(4-chloro-2-fluorophenyl)-5-[4-fluoro-3-(3-fluoro-pyridin-2-yl)phenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.30-7.35 (2H, m), 7.40-7.46 (2H, m), 7.53-7.61 (1H, m), 8.26 (1H, t, J8.2 Hz), 8.42-8.45 (1H, m), 8.54 (1H, dd, J 2.4, 6.6 Hz), 8.62 (1H, d, J 4.6 Hz), 9.69 (1H, s); m/z (ES+) 399.
Reaction SMILES: [CH:1]1([CH:4]2[N:9]=[C:8]([Cl:10])[C:7]([C:11]3[N:12](C(=O)C)[CH2:13][CH2:14][N:15]=3)=[C:6](Cl)[N:5]2[NH2:20])[CH2:3][CH2:2]1.[CH3:21][O-:22].[Na+]>CO>[Cl:10][C:8]1[C:7]([C:11]2[NH:12][CH2:13][CH2:14][N:15]=2)=[C:6]([O:22][CH3:21])[N:5]([NH2:20])[CH:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1
Reactant: C[O-]
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C2CC2)N=C1Cl
Agent: [Na+]
Solvent: CO
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C2CC2)N1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
3.0 g 2-cyclopropyl-4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 0.5 g sodium methylate in 30 ml methanol and stirred for three hours at room temperature. Then about 20 ml of methanol is distilled off. After adding water and extracting with chloroform, the organic phase is dried and concentrated. 1.9 g of 4-chloro-2-cyclopropyl-6-methoxy-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained; melting point 214° C. The hydrochloride obtained in known manner has a melting point of 200° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][CH:5]([CH2:4][CH2:3][CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)[O:6][CH2:7]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC1(C)COC(CCCBr)OC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCC(C)(C)CO3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]([CH3:21])[N:13]=1.S(Cl)([Cl:25])(=O)=O>C(O)(=O)C.O>[Cl:25][C:16]1[C:12]([C:3]2[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])=[N:13][N:14]([CH3:21])[C:15]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Reaction time: 6 h

Procedure:
To 5.00 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole dissolved in 50 ml of acetic acid was added 15 ml of sulfuryl chloride. The mixture was mildly refluxed with 2 ml portions of sulfuryl chloride added every 15 minutes. After 6 hours, the mixture was cooled, then diluted with water and extracted with ether. The ether was washed 3 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give a quantitative yield of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[CH3:32])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@H:27]3[CH3:32])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1COCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Potassium tert-butoxide (0.59 g) was added to a solution of 2-[benzyl({3-chloro-5-[(3R)-3-methylmorpholin-4-yl]pyrazin-2-yl}methyl)amino]ethanol (1.65 g) in DMF (50 mL) at 0° C., and the mixture was stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.32 g, 89%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31]#[N:32])=[CH:26][C:25]=3[S:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC>C(COC)OC>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31]4[NH:39][N:38]=[N:37][N:32]=4)=[CH:26][C:25]=3[S:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: c1ccc(CCN2C3CCC2CC(N2c4ccccc4Sc4cc(-c5nnn[nH]5)ccc42)C3)cc1
Temperature: 150 °C

Procedure:
To a solution of 10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile, 2aa (10 mg, 29 μmol) in dimethoxyethane was added trimethylsilyl azide (15 μL, 115 μmol) and dibutyltin oxide (1.5 mg), and the mixture was heated in a microwave for 15 min at 150° C. The mixture was allowed to cool to rt, and purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield title compound 10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine, 3aa as a TFA salt and as a mixture of endo and exo isomers. MS m/z (MH+) 481.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.N1C=CC=CC=1>[F:31][C:18]([F:17])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A portion of the raw N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (100 mg, 0.45 mmol) was dissolved in CH2Cl2/pyridine 9/1 (20 ml) and 4-(trifluoromethoxy)benzenesulfonyl chloride (100 μl, 0.58 mmol) was added dropwise. After stirring at room temperature over night, the reaction mixture was concentrated and the purification of the residue by chromatography on silica gel (CH2Cl2:CH3OH, 97:3) gave the title compound (94 mg, 47% for steps 31.4 and 31.5) as a gum.
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.C[O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]2[N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30](=[O:38])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)C=1O)=[O:13].Cl>CN(C=O)C.O>[OH:10][C:11]1[C:12]([O:13][CH3:4])=[CH:14][CH:19]=[CH:18][C:17]=1[C@H:16]1[CH2:20][C@H:21]1[C:22]1[N:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:30](=[O:38])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: COCC(=O)c1cccc(C=Cc2nc3ccccc3c(=O)n2-c2ccccc2)c1O
Reactant: C[S+](C)(C)=O
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc([C@H]2C[C@H]2c2nc3ccccc3c(=O)n2-c2ccccc2)c1O
Reaction time: 0.33 h
Yield: 15.2 %

Procedure:
NaOH (0.19 g, 4.8 mmol) was added to solution of trimethylsulfoxonium iodide (1.06 g, 4.8 mmol) in anhydrous DMF (20 mL) and stirred for 20 minutes. Then 69 (1 g, 2.4 mmol) was added in one portion and the reaction mixture was stirred for 2 hours at room temperature and left stirring overnight. The solution was poured into water, acidified by HCl to pH=6. The precipitate was filtered off and recrystallized from EtOH: H2O:DMF (1:1:1) mixture yielding 70 (0.14 g, 15%). M. Wt. 384. LCMS [M+H]+=385.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][C@@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13]O)([CH3:4])[CH3:3].S(Cl)(C)(=O)=O.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:3][C:2]([Si:5]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][C@@H:8]1[CH2:9][C@H:10]2[C@H:11]([CH2:12]2)[CH2:13][N:15]1[C:16]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25])([CH3:4])[CH3:1]
Reactant: CC(C)(C)[Si](OC[C@H](CC1CC1CO)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1C[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice cooled solution of phenylmethyl ((1S)-2-{[(1,1 dimethylethyl)(diphenyl)silyl]oxy}-1-{[2-(hydroxymethyl)cyclopropyl]methyl}ethyl)carbamate single diastereoisomer 1 D7 (1.18 g) in DCM (35 ml) and TEA (0.953 ml, 6.84 mmol) was added mesyl chloride (0.355 ml, 4.56 mmol) and the resulting mixture was stirred for 3 hours. After this time the solvent was removed under reduced pressure and the white solid obtained was dissolved in DMF (47 ml), the solution was cooled to 0° C. and NaH (0.730 g, 18.25 mmol, 8 eq) was added and ice bath was removed. After stirring overnight more NaH (0.365 g, 9.12 mmol, 4 eq) was added to the ice cooled mixture and stirred at room temperature for 3 hours. UPLC showed starting material and desired product in 1:1 ratio, so NaH (0.180 g, 4.5 mmol, 1.97 eq) was added at room temperature and stirred for 2.5 hours. A saturated solution of NH4Cl (300 ml) was added and extracted with EtOAc (3×50 mls), the organic phase was separated, dried (Na2SO4), filtered and evaporated to give a yellow oil which was purified via Biotage SP4 (silica gel, SNAP 100 g column; eluted with a gradient of Cy/EtOAc from 1/0 to 9/1). Collected fractions gave the title compound D8 (0.930 g) as a colourless oil. MS: (ES/+) m/z: 500 (M+1). C31H37NO3Si requires 499. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.76-7.31 (m, 15 H), 5.16-4.84 (m, 2 H), 4.37 (br.s, 1 H), 3.83-3.68 (m, 1 H), 3.68-3.52 (m, 2 H), 2.37-2.22 (m, 2 H), 1.39-1.18 (m, 1 H), 1.13-1.01 (m, 1 H), 0.95 (s, 9 H), 0.92-0.83 (m, 1 H), 0.79-0.70 (m, 1 H), 0.33-0.04 (m, 1 H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:15][CH:14]=2)[CH2:9]1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[K+].[K+].N>C1COCC1.CO.C(Cl)Cl.O>[CH2:33]([O:32][C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:20](=[O:21])[CH2:19][C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:11][CH2:12][C@H:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:3]4[CH3:2])[CH2:9]3)=[CH:18][CH:17]=2)[CH2:28][CH2:27]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(CC(=O)NC3CCNCC3)cc2)C1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCC(NC(=O)Cc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
2-[4-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-N-piperidin-4-yl-acetamide hydrochloride (0.51 g, 1.38 mmol) was dissolved in THF (20 mL) and water (5 mL) to form a clear solution. To this solution was added 0.30 g of ethyl chloroformate (3 mmol, 2 equiv), followed by K2CO3 (0.76 g, 5.52 mmol, 4 equiv). The clear solution was stirred at rt overnight. TLC (5% of 7N NH3 in MeOH/DCM) showed the SM was consumed completely. LCMS: a single peak at 2.559 with MS of 443 was detected. The two layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic solution was washed with brine (2×10 mL), dried (K2CO3), filtered, and concentrated. The crude product was purified on a 25-g silica gel column to get 0.42 g (69%) of the title compound as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C-:22]#[N:23].[K+].O1CCOCCOCCOCCOCCOCC1>C(#N)C>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][C:22]#[N:23])[CH:11]=3)[CH:7]=[CH:8]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CCl)cc32)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CC#N)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A solution of 6-chloromethyl-1-(4-methylphenylsulfonyl)indole (21.5 g) in acetonitrile (224 ml) was treated with potassium cyanide (8.8 g) and 1,4,7,10,13,16-hexaoxacyclooctadecane (3.6 g) and stirred at room temperature under a nitrogen atmosphere for 18 hr. The solution was poured onto ice and extracted with methylene chloride. The organic phase was washed with water and brine, dried (MgSO4) and evaporated. The resultant amber oil was purified by flash chromatography, eluting with 1:5 ethyl acetate:hexane, to give 1-(4-methylphenylsulfonyl)indole-6-acetonitrile (14.4 g, 76%) as a white powder; partial NMR (80 MHz, CDCl3): 2.34(s, 3H, ArCH3), 3.84(s, 2H, NCCH2), 6.62(dd, 1H, H3 -indole), 7.94(m, 1H, H7 -indole)
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:27][NH2:28]>>[CH3:27][NH:28][C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Product: CN[C@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (10.00 g, 26.63 mmol) and methylamine (50 mL, 2.0M solution in THF) was heated at 100° C. for 10 h in a sealed glass tube. The mixture was cooled to ambient temperature and concentrated under reduced pressure on a rotary evaporator. The crude product was treated with saturated NaHCO3 solution (50 mL) and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a dark-brown oil (3.50 g). The crude product was purified by repeated (twice) column chromatography on silica gel, eluting with chloroform-methanol (95:5, v/v). Selected fractions were combined, concentrated by rotary evaporation affording a light-brown oil (2.50 g). The oil was further purified by vacuum distillation using a short-path distillation apparatus, collecting 2.05 g (32.9%) of a colorless oil, bp 98-100° C. at 0.04 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1COC(c2ccc(F)cc2)=N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ccc(F)cc2)n1
Yield: 67.3 %

Procedure:
Benzoyl peroxide (0.49 g, 2.0 mmol) was added to a solution of methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.0 g, 40.3 mmol) in dry benzene (180 mL) and the mixture was refluxed for 15 min. N-bromosuccinimide (8.6 g, 48.3 mmol) was then added and the reaction mixture was refluxed for 2 h. The reaction mixture was quenched with ice-cold water and the crude product was extracted with EtOAc. The combined extracts were washed with 10% aqueous NaHCO3 solution, H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get methyl 2-(4-fluorophenyl)oxazole-4-carboxylate (6 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.14-8.10 (m, 2H), 7.19-7.15 (t, J=8.5 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z: Calculated for C11H8FNO3: 221.05. found: 221.8 (M+H)+
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]=[C:25]2[CH:33](O)[CH3:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[N:15]([CH:33]([C:25]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[N:26]=1)[CH3:34])=[N+:16]=[N-:17]
Reactant: CC(O)c1nc2cnccc2n1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2cnccc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 151.4 %

Procedure:
Diphenylphosphoryl azide (0.50 g, 1.81 mmol) and diisopropyl azadicarboxylate (0.61 g, 3.01 mmol) were added to a stirred solution of 1-(1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)ethanol (0.36 g, 1.50 mmol) and triphenylphosphine (0.79 g, 3.01 mmol) in dioxane (15 mL) at 0° C. under nitrogen. After addition the mixture was stirred at 20° C. for 16 h. Additional diphenyl phosphoryl azide (0.25 g, 0.91 mmol), triphenylphosphine (0.40 g, 1.53 mmol) and diisopropyl azadicarboxylate (0.30 g, 1.48 mmol) were added and the resultant mixture stirred at 20° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.60 g, contaminated with triphenylphosphine oxide). LCMS (method H): Rt 1.86 min, [M+H]+ 265