Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1
Reactant: Cc1cncc(C)c1
Reactant: BrCCCC/C=C\C=C/CCCCBr
Solvent: CC#N
Product: Cc1cc(C)c[n+](CCCC/C=C\C=C/CCCC[n+]2cc(C)cc(C)c2)c1
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 3,5-lutidine (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer.was washed extensively with ether until no 3,5-lutidine left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.29 (s, 4H), 7.99 (s, 2H), 6.12-6.18 (m, 2H), 5.30-5.38 (m, 2H), 4.31 (t, J=7.5, 4H), 2.30 (s, 6H), 2.05 (q, J=7.2, 4H), 1.81 (p, J=7.5, 4H), 1.24 (p, J=7.5, 4H). CNMR, 146.56, 140.96, 139.11, 132.28, 124.09, 61.49, 30.21, 26.34, 25.43, 17.73.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(O)cc1F
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-4-methylphenol and 4-fluorobenzaldehyde
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 80.8 %

Procedure:
Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (45 g, 0.33 moles) and 2-chloro-N,N-dimethylethylamine hydrochloride (14.2 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 7 days. More 2-chloro-N,N-dimethylethylamine hydrochloride (3 g, 20 mmoles) was added and stirring at room temperature was continued for 2 days. The reaction mixture was poured into water (600 mL) and extraction with ethyl acetate (2×200 mL), washing of the combined organic phases with water (200 mL), drying over MgSO4 and evaporation afforded 11.9 g (81%) of methyl 4-(2-dimethylaminoethoxy)benzoate as an oil.
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.O.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:2][C:3]2[N:11]=[CH:10][N:9]=[C:8]3[C:4]=2[NH:5][CH:6]=[N:7]3)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Sc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CSc2ncnc3nc[nH]c23)cc1
Yield: 91 %

Procedure:
After stirring a mixture of 30 mmol of 6-mercaptopurine monohydrate (5.12 g) and 30 mmol of water-free K2CO3 (4.12 g) in 25 mL of dry DMF for 5 minutes, 30 mmol of 4-nitrobenzylbromide (6.48 g) was added. After stirring for 4 h, 200 mL of H2O was added. The obtained solid was filtered and washed with EtOAc and CH2Cl2, followed by drying under vacuum. Yield: 91%.—White powder.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(CBr)ccc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1cc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)ccc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-(bromomethyl)-1-fluoro-2-methylbenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.43 (m, 1 H), 7.23-7.17 (m, 1 H), 7.17-7.03 (m, 3 H), 7.00-6.90 (m, 2 H), 6.30 (dd, J=3.3, 10.1 Hz, 1 H), 5.63-5.53 (m, 2 H), 5.49-5.38 (m, 1 H), 4.29 (t, J=4.9 Hz, 2 H), 2.97-2.82 (m, 2 H), 2.80 (s, 3 H), 2.25 (s, 3 H), 2.14-2.04 (m, 2 H), 1.03-0.91 (s, 9 H); LC/MS (m/z) ES+=517.38 (M+1).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]([C:21]1[CH:22]=[C:23]2[CH2:46][C@@:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:29]3=[O:45])[CH2:27][C:24]2=[N:25][CH:26]=1)([F:20])[CH2:18]O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl.[NH2:63][C@H:64]1[CH2:69][C@@H:68]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:67]([CH3:76])[N:66]([CH2:77][C:78]([F:81])([F:80])[F:79])[C:65]1=[O:82].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[F:20][C:17]([C:21]1[CH:22]=[C:23]2[CH2:46][C@@:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:29]3=[O:45])[CH2:27][C:24]2=[N:25][CH:26]=1)([F:16])[CH2:18][NH:63][C@H:64]1[CH2:69][C@@H:68]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:67]([CH3:76])[N:66]([CH2:77][C:78]([F:79])([F:80])[F:81])[C:65]1=[O:82]
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(C(F)(F)CO)cnc3C2)c2cccnc21
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NCC(F)(F)c2cnc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulfonic anhydride (0.056 mL, 0.335 mmol) was added to a cooled solution of (S)-3-(1,1-difluoro-2-hydroxyethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 10) (0.100 g, 0.223 mmol) and 2,6-di-tert-butyl-4-methylpyridine (0.070 g, 0.335 mmol) in CH2Cl2 (3 mL) at −78° C. The resulting mixture was warmed slowly to ambient temperature and stirred for 18 h. The reaction was diluted with EtOAc (100 mL), filtered through a pad of Celite®, washing with EtOAc, and concentrated to dryness in vacuo. The crude product dissolved in CH2Cl2 (3 mL) at ambient temperature. To this solution was added (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one HCl salt (described in Intermediate 11) (0.033 g, 0.104 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.190 mmol). The resulting mixture was stirred at ambient temperature for 18 h before being partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—80:20 to 0:100, to give the title compound MS: m/z=716.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2c(c1)N(c1ccccc1)C(=O)Cc1nnc(C)n1-2
Agent: [Na+]
Solvent: CO
Product: Cc1nnc2n1-c1ccc(S(C)=O)cc1N(c1ccccc1)C(=O)C2

Procedure:
3.36 g of 1-methyl-8-(methylthio)-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C. for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on silica gel (20-1000μ plates, 20×20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[CH:18]=2)[CH2:12]1.O=S(Cl)[Cl:37]>C(Cl)(Cl)Cl>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20]([CH3:33])[C:19](=[O:34])[C:18]=2[Cl:37])[CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: O=C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Cl)c(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 4 (40 mg, 0.1 mmol) in CHCl3 (2 mL) was treated with SOCl2 (200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MS to give the title compound 7. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.73 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 5.32-5.42 (m, 2H), 3.43 (s, 3H), 3.33-3.40 (m, 2H), 3.17 (m, 2H), 2.87 (s, 1H), 2.08 (m, 1H), 1.70 (m, 1H), 1.32-1.43 (m, 2H). MS (ES) [m+H] calc'd for C18H21ClN5O2, 374.1. found, 374.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reactant: COCCl
Agent: CCNC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed-under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purfied by flash chromatography (silica, ethyl acetate:hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2].[I:18][CH2:19][CH3:20]>>[I-:18].[CH2:19]([N+:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[NH:3][CH:1]=[O:2])[CH3:20]
Reactant: O=CNc1ccccc1CCc1ccccn1
Reactant: CCI
Product: CC[n+]1ccccc1CCc1ccccc1NC=O
Product: [I-]

Procedure:
A solution of 2-(o-formamidophenethyl)pyridine (36.1 g., 0.159 mole) and iodoethane (30.0 g., 0.191 mole) in Ch3CN (450 ml.) heated at reflux for 18 hr., cooled and diluted to incipient turbidity provides 1-ethyl-2-(o-formamidophenethyl)pyridinium iodide, yield, 44.8 g. (74%), m.p. 155°-157° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]([O:22]C)=[O:21])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[Si:1]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]([OH:22])=[O:21])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 1-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3600 mg, 10.6 mmol) in THF (10 mL) and MeOH (5 mL) was added NaOH (3181 μl, 31.8 mmol). The solution was stirred at 23° C. for 48 h and was partitioned between CH2Cl2 and 10% citric acid (aq. pH˜4). The aqueous was extracted with CH2Cl2 (3×50 mL). The combined organics were dried with brine and MgSO4, and concentrated to a yellow solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 326. Calc'd exact mass for C16H27NO4Si: 325.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[OH-].[Na+].[CH2:23](O)[CH3:24]>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[C:18]([CH2:13][C:12]5[CH:4]=[N:5][CH:6]=[C:23]([CH3:24])[CH:11]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(=O)c(Cc3cncc(C)c3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 101, step 6 was suspended in ethanol (18 ml), and 5-methylnicotinic aldehyde (176 mg) prepared in accordance with the procedure described in J.O.C., 53, 3513 (1988) and sodium hydroxide (291 mg) dissolved in water (1.5 ml) were added to the suspension at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (312 mg, 79%).
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1.C(Cl)Cl.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.O>[F:1][C@H:2]1[C@H:6]([O:7][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccc4ccccc4c3)C[C@H]2F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A flask was charged with (trans)-naphthalen-2-ylmethyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (237 mg, 0.819 mmol), TEA (0.343 ml, 2.458mmol) and DMAP (10.0 mg, 0.082 mmol) in DCM (4.3 ml, 0.86 mmol). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (234 mg, 1.23 mmol) was added. The reaction was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluting with 0-5% MeOH in DCM to give the product as an oil (160 mg, 44% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](OC(C)(C)C)=[O:29])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:75]([O:79][C:80]([NH:82][C:83](C)([CH3:87])[C:84](O)=O)=[O:81])([CH3:78])([CH3:77])[CH3:76]>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:29])[C:83]([NH:82][C:80](=[O:81])[O:79][C:75]([CH3:76])([CH3:78])[CH3:77])([CH3:87])[CH3:84])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (17-2,276 mg, 0.683 mmol, 1 equiv), triethylamine (277 mg, 2.73 mmol, 4 equiv), PYBOP (711 mg, 1.37 mmol, 2 equiv) and 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (278 mg, 1.37 mmol, 2 equiv) in in DMF (10 mL) was warmed at 60° C. for 18 hours. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes gave tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]-1,1-dimethyl-2-oxoethylcarbamate (17-3) as a pale yellow gum. LRMS m/z (M+H) 588.9 found, 589.0 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.O[Li].O.Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:14])([F:13])[F:15])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To 180 mg (0.42 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 100 mgs of LiOH—H2O and 5 mL of a solvent mixture of THF/MeOH/H2O (7:2:1). The mixture was heated to reflux for 30 min. and allowed to cool to rt. After standing overnight, the mixture was concd in vacuo, treated with 20 mL 1N HCl and allowed to stir. The mixture was extracted three times with Et2O, the combined extracts dried and concd in vacuo to give 150 mgs (88.3%) of an off-white solid: 1H NMR (CDCl3/d6-acetone/400 MHz) 5.86 (q, 1H, J=6.7 Hz), 7.60 (s, 1H), 7.70 (s, 1H), 7.75 (s, 1H); 19F NMR (CDCl3/d6-acetone/400 MHz) −79.2 (d, 3F, J=6.8 Hz); MS(ESI+) 405 (M+1, 100, one Cl pattern); HRMS (ES-) m/z calcd for (C11H4O3IClF3) 402.8840, found 402.8850.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12](I)=[C:11]([NH2:20])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:27]#[N:28])#[CH:23].C(NC(C)C)(C)C.CN(C)C=O>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:20][C:11]1[N:10]=[C:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12]=1[C:23]#[C:22][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[C:26]([C:27]#[N:28])[CH:25]=1
Reactant: C#Cc1cc(F)cc(C#N)c1
Reactant: CN(C(=O)OC(C)(C)C)c1nc(N)c(I)c2c1ncn2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1nc(N)c(C#Cc2cc(F)cc(C#N)c2)c2c1ncn2C
Temperature: 90 °C

Procedure:
A1.12 tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate (3.2 g, 7.9 mmol), dichlorobis(triphenylphosphine)palladium (270 mg, 0.38 mmol), 3-ethynyl-5-fluorobenzonitrile (C1.2) (1.5 g, 10 mmol), CuI (75 mg, 0.39 mmol), diisopropylamine (15 mL) were added to N,N-dimethylformamide (15 mL). The reaction mixture was heated at 90° C. (in preheated oil bath) for 60 min. Additional 3-ethynyl-5-fluorobenzonitrile (C1.2) (0.5 g, 3.4 mmol) was added to the reaction mixture and heated for another 60 min. The reaction was cooled and diluted with ethyl acetate and washed several times with water. The solvent removed under reduced pressure and the residue was purified by silica gel column chromatography (50%-70% ethyl acetate/hexane) to give 3.0 g (90%) of C1.3. LCMS B: Ret time 2.98 min, (M+H)+=421.31, 1H NMR, 400 MHz, CDCl3: 7.62 (s, 1H), 7.57 (s, 1H), 7.42 (dm, 1H), 7.35 (dm, 1H), 5.00 (bs, 2H), 4.05 (s, 3H), 3.39 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:18]([NH2:20])=O>CN(C)C=O.C(O)=O>[NH2:8][C:7]1[C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:2]=2[N:1]=[CH:18][N:20]=1
Reactant: Cc1c(C#N)c(N)n(-c2ccc(Cl)cc2)c1C
Reactant: NC=O
Solvent: O=CO
Solvent: CN(C)C=O
Product: Cc1c(C)n(-c2ccc(Cl)cc2)c2ncnc(N)c12

Procedure:
15 g (0.06 mol) of 2-amino-1-(4-chlorophenyl)-3-cyano-4,5-dimethylpyrrole in 100 ml of formamide, 30 ml of dimethylformamide and 15 ml of concentrated formic acid are heated under reflux for 7 hours. The crystals which precipitate on cooling are washed with water and recrystallised from ethanolic potassium hydroxide solution. Melting point: 250° C., yield: 13 g (79% of theory).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]1[C@H:9]([C:10]([NH:12][C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.CC(C)=[O:23].[ClH:25]>O>[CH3:1][CH2:2][CH2:3][NH+:4]1[C@H:9]([C:10]([NH:12][C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH2:23].[Cl-:25]
Reactant: CC(C)=O
Reactant: CCCN1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Reactant: Cl
Solvent: O
Product: CCC[NH+]1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Product: [Cl-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
About 2 g of Ropivacaine base was dissolved in a mixture of 2.6 mL of concentrated hydrochloride acid and 5 mL of water at about 30° C. This mixture was stirred at a temperature of about 50° C. for about 30 min and then hot acetone (100 ml) was added. The mixture was then held at about 0 to 5° C. and stirring continued for about 2 hr. A precipitated solid was filtered, washed with acetone, and then dried under vacuum at about 35° C. for about 6 hr. 2.1 g, yield 93%, water content: 5.5%. All water contents herein are determined by Karl Fisher titration.