Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[N:50]1([C:56]2[CH:64]=[CH:63][C:59]([C:60]([OH:62])=O)=[CH:58][N:57]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:60](=[O:62])[C:59]2[CH:63]=[CH:64][C:56]([N:50]3[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]3)=[N:57][CH:58]=2)[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=C(O)c1ccc(N2CCCCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
3,5-Dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (Compound E of Example 184, 0.04 g, 0.066 mmol, 1 eq) was dissolved in acetonitrile. DIPEA (0.034 mL, 0.198 mmol, 3 eq) was added followed by 6-(piperidin-1-yl)nicotinic acid (0.013 g, 0.066 mmol, 1 eq), EDCI (0.018 g, 0.099 mmol, 1.5 eq) and HOBT (0.013 g, 0.099 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 12 h and concentrated to remove the volatiles. The residue obtained was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (0.03 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 0.74 (t, 6H), 1.50-1.59 (m, 6H), 1.9-2.0 (s, 1H), 3.03-3.04 (t, 2H), 3.54-3.55 (t, 4H), 4.45-4.49 (m, 6H), 6.82-6.84 (d, 1H), 6.9 (t, 1H), 7.03-7.05 (m, 2H), 7.14-7.28 (m, 6H), 7.42-7.44 (d, 2H), 7.53-7.61 (m, 4H), 7.80 (s, 1H), 8.12 (s, 1H). MS (ESI): 788.6 (M−H)−.
Reaction SMILES: II.Br[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([F:11])[CH:5]=1.CON(C)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[F:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[CH:7]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: Cc1cc(F)cc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: II
Solvent: C1CCOC1
Product: Cc1cc(F)cc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -78 °C
Yield: 99.4 %

Procedure:
A 100 mL three-neck flask was charged with Mg (638 mg, 26.6 mmol), a small crystal of iodine. The flask was degassed and refilled into N2. A solution of 1-bromo-3-fluoro-5-methyl-benzene (5 g, 26.6 mmol) in anhydrous THF was added. The reaction mixture was stirred and heated to reflux for 2 h. Once most of the Mg disappeared the reaction was cooled to −78° C. Then (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1.45 g, 5.32 mmol) in anhydrous THF was added dropwise slowly, and the mixture was stirred overnight. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product (R)-tert-butyl 3-(3-fluoro-5-methylbenzoyl)piperidine-1-carboxylate (1.7 g, 99%), which was used immediately without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Br:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCNc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 103.4 %

Procedure:
To a solution of N-ethylaniline (10.0 g) in DMF (50 ml) was added dropwise at room temperature a solution of N-bromosuccinimide (14.69 g) in DMF (100 ml), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-N-ethylaniline (17.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([C:20]([O:22]C)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(C(=O)O)C1
Yield: 68.2 %

Procedure:
To a solution of 89 mg of methyl ester (from Example 104, Step B) in 1.5 mL EtOH was added 1.0 mL of 0.5N NaOH. After 36 h the reaction was concentrated under vacuum. The residue was dissolved in 25 mL H2O and washed with 25 mL Et2O. After separating layers, the aqueous phase was acidified to pH 2 using 0.5N KHSO4. The aqueous phase was extracted with 3×25 mL of CH2Cl2. The combined extracts were dried over Na2SO4 and concentrated under vacuum to give 58 mg of a white foam which was taken on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][C:3]=1[O:22][CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:34][C:35]1[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:21][Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=2)[N:8]([C:40]([C:38]2[S:39][C:35]([Cl:34])=[CH:36][CH:37]=2)=[O:41])[C:7]=1[CH3:11]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COc1cc2c(CC(=O)OCC[Si](C)(C)C)c(C)[nH]c2cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc2c(CC(=O)OCC[Si](C)(C)C)c(C)n(C(=O)c3ccc(Cl)s3)c2cc1F
Reaction time: 0.5 h

Procedure:
In a dry flask 2-trimethylsilylethyl (6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl)acetate (4, R1═H═B, R2═CH3, R3═F, R4═CH2CH2Si(CH3)3), (1.0 g, 2.96 mmol) was dissolved in tetrahydrofuran (THF) (10 mL) and hexamethylphosphoramide (HMPA) (1 mL) and cooled to −78° C. Potassium bis(trimethylsilyl)amide 0.5M in toluene (6.52 mL) was added and the reaction was stirred for 30 minutes. 5-Chlorothiophene-2-carbonyl chloride (562 mg, 3.1 mmol) in 3 mL of THF was added and the reaction was stirred for 0.5 hours at −78° C. and 0.5 hours at 0° C., and then treated with saturated ammonium chloride (20 mL) and the reaction extracHted with ethyl acetate (3×30 mL), dried over MgSO4 and concentrated to give a thick oil which was purified by chromatography to afford 2-trimethylsilylethyl-{1-[(5-chlorothien-2-yl)carbonyl]-6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl}acetate (5, R1═H═B, R2═CH3, R3═F, R4═CH2CH2Si(CH3)3, A=5-chlorothiophene). (600 mg, 1.24 mmol, 42%, >99% pure) as light yellow oil; 1H-NMR (CDCl3/300 MHz) consistent with the assigned structure.
Reaction SMILES: Br[C:2](=[CH:6]OCC)[C:3](=[O:5])[CH3:4].Cl.[OH:11][CH2:12][C:13]([NH2:15])=[NH:14].CN(C)C(N(C)C)=N>CC(C)=O>[OH:11][CH2:12][C:13]1[NH:14][CH:6]=[C:2]([C:3](=[O:5])[CH3:4])[N:15]=1
Reactant: N=C(N)CO
Reactant: CCOC=C(Br)C(C)=O
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1c[nH]c(CO)n1
Reaction time: 48 h
Yield: 21 %

Procedure:
9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-buten-2-one was combined with 5.53 (0.05 mol) of hydroxyacetamidine hydrochloride in 100 ml acetone to form a slurry. To the slurry at 25° was added 11.5 g (0.1 mol) of 1,1,3,3-tetramethylguanidine over a period of 5 minutes. After stirring for 48 hours the slurry was filtered and the mother liquors were concentrated in vacuo to an oil which was chromatographed on silica gel 60 (E. Merck) using chloroform as eluent to give 1.48 g (21%) of 2-hydroxymethyl-4-acetylimidazole, mp 147°-148° . nmr (DMSO-d6) (δ): 7.73 (s, 1H); 5.46 (very broad s, 1H); 4.5 (broad s, 2H); 2.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].O.Cl.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH2:9][OH:18])=[N:6][CH:7]=1
Reactant: Cc1c(Br)c[n+]([O-])c(C)c1Cl
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)cnc(CO)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
To a solution of 5-bromo-3-chloro-2,4-dimethylpyridine 1-oxide (373 mg; 1.5772 mmol) in dichloromethane (10 mL; 156.0 mmol) was added trifluoroacetic anhydride (0.70 mL; 5.0 mmol). The reaction mixture was stirred at room temperature for 20 hours. Trifluoroacetic anhydride (0.5 mL; 4 mmol) was then added and the reaction mixture stirred for an additional 4 hours at room temperature. The reaction mixture was poured into 2M aqueous potassium carbonate and extracted twice with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate, filtered, and evaporated in vacuo. The resulting residue was dissolved in tetrahydrofuran (6 mL), and treated with sodium hydroxide (10 mol/L) in water (0.60 mL; 6.0 mmol). The mixture was stirred at room temperature for 2 hours, and then neutralized with 5M aqueous HCl (1.3 mL). The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 20-100% ethyl acetate in dichloromethane) to yield 255.6 mg (69%) of the title compound. LCMS (ESI): M+H=236.2; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 4.73 (d, J=4.8 Hz, 2H), 4.05 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:11](=O)([O-])[OH:12].[Na+]>C=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][OH:12]
Reactant: Cn1cnc2ccccc21
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Product: Cn1c(CO)nc2ccccc21
Temperature: 25 °C

Procedure:
1-Methylbenzimidazole (5.0 g, 0.038 mol) was stirred at reflux in 37 wt % aqueous formaldehyde (50 ml) for 24 h. The solution was allowed to cool to room temperature then basified with saturated sodium hydrogen carbonate solution and then extracted with. dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 2.5 to 10% methanol in dichloromethane. The resultant semi-solid was triturated with isohexane to yield a solid, which was then recrystallised from ethyl acetate/isohexane, yielding (1-methyl-1H-benzimidazol-2-yl)methanol as a white solid (0.71 g). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 3.81 (3H, s), 4.89 (2H, s), 7.26 (3H, m), 7.69 (1H, m); MS (ES+) m/e 163 [MH]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([OH:13])=O)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(O)=O>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]([N:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[O:13])[CH2:9]2
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C(C1C2CC3CC(C2)CC1C3)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 24.2 mg (0.134 mmol) adamantane-2-carboxylic acid, 20 mg (0.168 mmol) indoline, 64.7 mg (0.2 mmol) TBTU and 43.4 mg (0.336 mmol) DIPEA in 1 mL DMF was stirred at room temperature overnight. Formic acid was added and the mixture was subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 14.1 mg (30%) of the title compound. MS(m/e): 282.4 (MH+).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19]>C(Cl)(Cl)Cl>[C:18](=[O:19])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[O:20][CH:21]([Cl:23])[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a ice cooled mixture of 27.8 g of p-nitrophenol, 16.0 g of pyridine and 1 L of chloroform is added, dropwise, 34 g of alpha-chloroethyl chloroformate. After 1 hour, the ice bath is removed and the reaction is stirred for 16 hours at room temperature. The mixture is washed with water, 0.5% sodium hydroxide and water. The organic layer is dried and concentrated in vacuo to give 47.85 g of the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.Cl>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (110 mg) obtained in Example 40 was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 85:15 mixed solvent of methylene chloride and methanol, and water were added to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:3) to obtain a pale yellow foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (63 mg).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4/[CH:43]=[CH:44]\[C:45]([O:47][CH3:48])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH3:48][O:47][C:45]([CH:44]1[CH2:7][CH:43]1[C:38]1[C:37]2[C:41](=[C:33]([C:30]3[N:29]=[C:28]([C:20]4[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:26])[CH3:27])=[C:18]([Cl:17])[CH:19]=4)[O:32][N:31]=3)[CH:34]=[CH:35][CH:36]=2)[N:40]([CH3:42])[CH:39]=1)=[O:46]
Reactant: COC(=O)/C=C\c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1CC1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C

Procedure:
To a suspension of trimethylsulfoxonium iodide (234 mg) in DMSO (3 mL) stirred under nitrogen at 20° C. was added NaHMDS (1.0 mol/L in THF, 1.0 mL) dropwise during 5 mins. The reaction mixture was stirred at this temperature for 15 mins. A solution of methyl (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D63) (120 mg) in DMSO was added dropwise. After addition was complete, the reaction was stirred at room temperature for 1.5 h, and then warmed to 50° C. for 4 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, aqueous HCl (2 M) and brine, dried over sodium sulphate and evaporated to afford methyl-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D65) (100 mg). MS (ES): C25H24ClN3O4 requires 465. found 466.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][S:26]2(=[O:33])=[O:32])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Yield: 92.5 %

Procedure:
Reaction of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (2.21 g, 6.03 mmol) and [1,2]thiazinane 1,1-dioxide (0.97 g, 7.2 mmol) in dry N,N-dimethylformamide (30 ml) with sodium hydride (0.35 g of a 60% dispersion in mineral oil, 8.8 mmol) gave 2.35 g (92% yield) of the title ester as white needles; mp 109–110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.29 (3H, t, J=7.1 Hz, CH3), 1.62 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.15–3.21 (1H, m, CH), 3.5–3.6 (1H, m, CH), 3.64 (3H, s, NCH3), 3.64 (1H, m overlapping with NCH3, CH), 3.97–4.05 (1H, m, CH), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.29 (2H, AB system, JAB=10.6 Hz, Δν=62.5 Hz, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C19H23N3O6S: C 54.15, H 5.50, N 9.97. Found: C 53.88, H 5.40, N 9.91.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=[O:32])(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:31]([C:30]3[CH:34]=[CH:35][N:36]=[C:28]([NH:27][C:24](=[O:26])[CH3:25])[CH:29]=3)=[O:32])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccnc(NC(C)=O)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2-acetylamino-isonicotinic acid to yield (3aR,4S,7aR)-4-(2-acetylamino-pyridine-4-carbonyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 476; RT=7.443 min HPLC Method I
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([F:18])=[C:11]([CH2:13]N(OC)C)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[O-].[Na+].S1C=C(C=[O:29])N=C1.[BH4-].[Na+].Cl>C1COCC1.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([F:18])=[C:11]([CH2:13][OH:29])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)Cc1nc(NC(=O)OC(C)(C)C)sc1F
Reactant: O=Cc1cscn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(CO)c(F)s1
Yield: 45 %

Procedure:
A solution of Intermediate 104: {5-Fluoro-4-[(methoxy-methyl-amino)-methyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (7.5 g, 25.7 mmol) in THF (45 mL) and water (4.5 mL) was rapidly stirred and treated slowly dropwise with 6.15% sodium hypochlorite solution in water (Clorox™, 67 mL, 55 mmol). The resulting thiazole-4-carboxaldehyde was reduced in situ with sodium borohydride (0.5 g). The reaction was acidified with 2 N HCl (10 mL) and extracted with diethyl ether (2×50 mL). The extracts were dried with sodium sulfate and evaporated to leave an orange resin which purified by silica gel chromatography (80% EtOAc/hexane) to afford (4-hydroxymethyl-5-fluoro-thiazol-2-yl)-carbamic acid tert-butyl ester as a yellow foam (2.9 g, 45% yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH2:21][OH:22])=[N:13]1.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH3:11][N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH:21]=[O:22])=[N:13]1
Reactant: Cn1cc2c(CO)cccc2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1cc2c(C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Under nitrogen atmosphere, dimethyl sulfoxide (70.0 mL, 987 mmol) was added to a solution of oxalyl chloride (43.2 mL, 493 mmol) in dichloromethane (2.47 L) at −78° C., and the mixture was stirred for 2 hr. To the reaction mixture was added (2-methyl-2H-indazol-4-yl)methanol (40.0 g, 247 mmol), and the mixture was stirred for 1 hr. To the reaction mixture was added triethylamine (139 mL, 987 mmol) at −78° C., and the mixture was stirred for 1 hr and warmed to room temperature over 4 hr. To the reaction mixture was added aqueous ammonium is chloride solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (dichloromethane/hexane) to give the title compound (36.3 g, yield 92%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10]OCCOC.C([Li])CCC>CCCCCC.CCOCC>[CH3:10][O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1]
Reactant: COCCOC
Reactant: C#CCC(O)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C#CCC(CCCC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.26 parts of 1-octyn-4(RS)-ol in 10 parts by volume of ethylene glycol dimethyl ether, cooled to about -40° is added dropwise 4 parts by volume of 2.5 M n-butyl lithium in hexane. The cooling bath is removed and 4 parts of trimethyloxonium hexafluorophosphate is added. The resulting reaction mixture is stirred at room temperature for about 1 hour, then is diluted with ether, washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 1-octyn-4(RS)-ol methyl ether.