Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[Na+]>C(O)C.CN(C=O)C>[C:25]([CH2:24][CH2:23][CH2:22][S:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:5]([CH3:7])[N:6]=1)([OH:27])=[O:26]
Reactant: CCOC(=O)CCc1sc(S)nc1C
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(SCCCC(=O)O)sc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
2 g (8.6 mmol) of ethyl 3-[2-mercapto-4-methyl-1,3-thiazol-5-yl]propionate were initially introduced into 40 ml of dry DMF, and 1.48 g (11 mmol) of powdered K2CO3 and 1.23 ml (8.6 mmol) of ethyl 4-bromobutyrate were added, and the reaction mixture was stirred at 50° C. for 2 hours. A solid residue was filtered off with suction, the DMF was removed in vacuo, and 3.6 g of a crude product were obtained, and this was taken up in 25 ml of ethanol. After addition of 1N sodium hydroxide solution, the mixture was stirred at room temperature for 2 hours, and the ethanol was removed in vacuo, and the aqueous residue was adjusted to pH 3 with hydrochloric acid. The solution was extracted with ethyl acetate, and the organic phase was dried with MgSO4 and evaporated. 2.2 g (88%) of the title compound were obtained as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([N:13]2[CH2:18][CH2:17][C:16](O)([C:19]#[N:20])[CH2:15][CH2:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[C:8]([N:13]2[CH2:14][CH:15]=[C:16]([C:19]#[N:20])[CH2:17][CH2:18]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(O)CCN(c2ncccc2Cl)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., phosphoryl trichloride (10 g, 68 mmol) was slowly added into a solution of 1-(3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonitrile (compound 22) (8 g, 33 mmol) in pyridine. After stirred at RT for 30 minutes, the reaction was washed by a HCl solution, and extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[O:37])=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)NC(C)(C)CO)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 22.8 %

Procedure:
To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 20 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g). In a manner similar to the method described in Examples 1e, rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2-methyl-1-propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([SH:38])[NH:28][C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1.[OH-].[Na+]>S(=O)(=O)(O)O.O.CN(C)C=O.C(Cl)Cl.[Cu]>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]2[N:28]=[C:27]([S:38][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:26][C:25]=2[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: O=N[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccccc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
1.5 g of aniline is dissolved in 2.0 g of concentrated sulfuric acid and 30 ml of water and, after the addition of 10 g of ice, diazotized at 0° with a solution of 1.2 g of sodium nitrite in 10 ml of water. The diazonium salt solution is then neutralized with sodium acetate and introduced at 5° under thorough agitation into a solution of 5.02 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in 200 ml of dimethylformamide containing 10 ml of water, 1.93 g of sodium hydroxide solution, as well as 1.15 g of powdered copper. The mixture is further stirred for 20 minutes, poured into 600 ml of water, the thus-precipitated oil is taken up in methylene chloride, the organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 200 g of silica gel. Elution with acetone/hexane 2:3 yields 2.47 g of 4,5-bis(4 -methoxyphenyl)-2-(phenylthio)imidazole, mp 177°-179° after recrystallization from hexane/ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:16]1[CH2:20][N:19]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[C:18](=O)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:16]1[CH2:17][CH2:18][N:19]([C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(NC(=O)OC(C)(C)C)c2ccccc2)CC1=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@@H](C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.2 %

Procedure:
Under a nitrogen atmosphere, 1 mol/l borane-tetrahydrofuran complex (4.6 ml) was added dropwise to a tetrahydrofuran solution (10 ml) of 4-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (600 mg, 1.52 mmol) under ice cooling, followed by stirring at room temperature for 13 hours. After removal of the solvent under reduced pressure, 80% water-containing ethanol (15 ml) and triethylamine (3 ml) were added to the residue and the mixture was heated under reflux for 5 hours. After cooling on standing, the solvent was removed under reduced pressure and chloroform (30 ml) was added to the residue. The solution was washed with water (10 ml) and saturated saline (10 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Elution with chloroform/methanol (20/1) afforded the title compound (510 mg, 88%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2C=C(N)NN=2)C[CH2:26]1>>[CH:1]1([C:2]2[CH:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:26][CH2:25]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Cc1cc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Product: O=Cc1ccc(-c2nc3cc(C4CC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde by using 3-cyclopropyl-1H-pyrazol-5 amine in the first step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[N:17]1[CH:22]=[N:21][N:20]=[CH:19][N:18]=1>O1CCOCC1>[N:17]1[CH:22]=[N:21][N:20]=[CH:19][N:18]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:12]([Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:19][N:18]=[N:17][CH:22]=1
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Agent: c1nncnn1
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cnncc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
A solution of 1,2,4,5-tetrazine (0.53 M in dichloromethane) was prepared by the method of H. C. van der Plas et al. (J. Heterocycl. Chem., 1987, 24, 545-548). (2-Fluoro-5-nitrophenylethynyl)trimethylsilane (8.8 g, 37.1 mmol) and 1,4-dioxane were added to a solution of 1,2,4,5-tetrazine (35 ml, 18.6 mmol, 0.53 M in dichloromethane). The dichloromethane was distilled off and the dioxane solution was stirred at reflux for 36 h. The solvent was removed to leave a brown oil. Purification by chromatography (silica gel, 0-1% MeOH/CH2Cl2) gave 4-(2-fluoro-5-nitrophenyl)-5-trimethylsilanylpyridazine as a brown oil: MS (ES+) m/z 292 [M+H]+ and 249 [M−3CH2]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7](C=O)[CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OC)(C)(C)C.O>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CN(C=O)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: C=CNC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of N-formyl-N-vinyl-carbamic acid tert-butyl ester (103.6 g, crude 89% pure, 539 mmol) in THF (320 ml) was cooled to 0° C. and stirred rapidly. NaOH (2M, 323 ml, 6.46 mmol) was slowly added over ca 20 minutes. The internal temperature rose to 19° C., and began then to cool. After cooling to 5° C. the mixture was warmed to RT. After 1 hour the reaction was finished according to tlc and GC. The reaction mixture was shaken between tBuOMe (250 ml) and water (250 ml), washed with water (250 ml) and brine (250 ml), dried over MgSO4 and evaporated. The product was a yellow oil containing traces of THF (NMR). The crude product was dissolved in pentane (25 ml), seeded, and left overnight at −20° C. The colourless crystals were swirled in pentane, filtered off and washed 3× with pentane, then spread in the air to dry to yield 48.9 g (63%). The mother liquors were evaporated down, dissolved in a little pentane and seeded. A further 8.1 g (11%) was isolated. (The product can also be sublimed/distilled.) m.p. 67-68° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2csc(NC(C)=O)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 5.0 g of 2-amino-4-(5-acetylaminomethyl-2-thienyl]thiazole in 200 ml of chloroform is added 12 ml of triethylamine, and is added dropwise 1.7 g of acetyl chloride with stirring at room temperature. The whole mixture is stirred at room temperature for an hour. After completion of the reaction, the resultant mixture is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the residue is crystallized from ethanol, the crystals are collected by filtration and recrystallized from ethanol to give 2-acetylamino-4-(5-acetylaminomethyl-2-thienyl)thiazole, melting at 251° C. with decomposition.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[C:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[C:20]([C:31]([F:34])([F:33])[F:32])=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]3)[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].C(O)C.C([BH3-])#N.[Na+]>>[C:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[C:20]([C:31]([F:32])([F:33])[F:34])=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([CH2:29][NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[CH:23]=[CH:22]3)[CH2:14][CH2:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: NCCS(=O)(=O)O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCS(=O)(=O)O)ccc3c2C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
Taurine (0.03737 g, 0.2986 mmol) was added to a solution of 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (0.1130 g, 0.2986 mmol) in Ethanol (3.00 mL, 51.4 mmol) and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature and Sodium cyanoborohydride (0.02252 g, 0.3583 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature, washed with saturated aqueous citric acid solution (4 ml), then concentrated to dryness under reduced pressure. The resulting solid was washed with water and filtered. The residue was washed with water (10 mL), ether (10 mL) and hexane (10 mL) consecutively, then filtered. The residue was purified by prep HPLC to give the title compound. ESI-MS(M+H+): 488.3; 1H NMR (400 MHz, DMSO-d6) Shift 8.46-8.52 (m, 1H), 7.83-7.88 (m, 1H), 7.73-7.80 (m, 2H), 7.35-7.40 (m, 2H), 4.21-4.30 (m, 1H), 4.02 (br. s., 2H), 2.88 (t, J=6.78 Hz, 2H), 2.50 (d, J=13.80 Hz, 2H), 1.77-1.85 (m, 2H), 1.43-1.52 (m, 2H), 1.00-1.13 (m, 2H), 0.67-0.92 (m, 3H), 0.53 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]3[NH:25][N:26]=[N:27][N:28]=3)=[CH:37][CH:38]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2]
Reactant: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure from Example 13, 5-cyano-4-(2,5-dichloro-1H-pyrrol-1-yl)-2-propylimidazole (Example 30) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:16][S:17][CH:18]=1.CN([CH:30]=[O:31])C>C1COCC1>[Br:13][C:14]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:16][S:17][C:18]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-c2cscc2Br)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2csc(C=O)c2Br)cc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of diisopropylamine (1.2 g, 11.4 mmol) in 20 mL of anhydrous THF was added n-BuLi (3.7 mL, 2.5 M in hexane) at −78° C. After the mixture was stirred at this temperature for 0.5 h, a solution of 4-(4-bromothiophen-3-yl)benzonitrile (prepared in Step 1 of Compound 2) (2.0 g, 7.6 mmol) in anhydrous THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 15 min., a solution of DMF (611 mg, 8.4 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h, and at room temperature for 2 h. The mixture was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc, concentrated, and purified by column chromatography on silica gel to give 4-(4-bromo-5-formylthiophen-3-yl)benzonitrile (600 mg, yield 27%).
Reaction SMILES: CC(C)[C@H](NS(C1C=CC(C)=CC=1)(=O)=O)CO.[CH:18]1([CH:24]=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=[C:41]([O:47][CH3:48])[O:42][Si](C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.O1CCCC1>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([C@@H:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[OH:25])[C:41]([O:47][CH3:48])=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CC1CCCCC1
Reactant: COC(=Cc1ccccc1OCc1ccccc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)N[C@H](CO)C(C)C)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](c1ccccc1OCc1ccccc1)[C@H](O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dry ice-acetone bath cooled 1.45M solution of lithium diisopropylamide in a mixture of tetrahydrofuran and n-hexane (1.4 ml) was added methyl (2-benzyloxyphenyl)acetate (256 mg). The mixture was stirred for 30 minutes at the same temperature and then for 30 minutes at 0° C. After cooling the solution to −78° C. chlorotrimethylsilane (0.3 ml) was added and the mixture was allowed to warm to room temperature. The solution was diluted with n-hexane (50 ml), filtered through celite, and concentrated under reduced pressure to afford 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene. To an ice bath cooled solution of (2S)-3-methyl-2-(p-tolylsulfonylamino)butanol (288 mg) in dichloromethane (10 ml) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. After cooling the solution to −78° C., cyclohexanecarbaldehyde (112 mg) and a solution of 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene prepared above in dichloromethane (1 ml) were added. The solution was stirred for one hour at −78° C. and then quenched by an aqueous solution of sodium bicarbonate at 0° C. The mixture was extracted with diethyl ether, dried and evaporated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (4 ml) and aqueous 1M solution of hydrochloric acid (2 ml), and the resulting solution was allowed to stand for 30 minutes. Aqueous solution of sodium bicarbonate was added thereto and the mixture was extracted with ether. The organic layer was dried and evaporated. Preparative thin layer chromatography [silica gel, ether - hexane (1:4)] afforded methyl (2R,3R)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (187 mg). High pressure liquid chromatography analysis (Daicel AD column eluting with 20% isopropyl alcohol - hexane) indicated an enantiomeric excess of 95% (Rt: major 10.51 minutes, minor 8.60 minutes).
Reaction SMILES: [N+:1]([C:4]1[C:11](C)=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[OH-].[Na+].[C:15]([Cl:19])(Cl)([Cl:17])[Cl:16]>[Cl-].C([N+](CC)(CC)CC)C.C(Cl)Cl>[N+:1]([C:4]1[C:5]([CH3:6])=[CH:8][CH:9]=[CH:10][C:11]=1[C:15]([Cl:19])([Cl:17])[Cl:16])([O-:3])=[O:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cccc(CBr)c1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1[N+](=O)[O-]
Yield: 36 %

Procedure:
1.5 gms of 2-nitro-3-methyl benzyl bromide was mixed with 0.05 gms of tetraethyl ammonium chloride in 15 ml of methylene chloride and 10 ml of carbon tetrachloride. 20 ml of 50% sodium hydroxide was added and the mixture refluxed for about 3 hours. After completion of the reaction, the organic layer was separated, washed with water, and the product separated to give 36% yield as determined by GC-Mass spectral analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:10]1[CH:11]=[CH:12][CH2:13][CH:14]1[C:2]1[CH:9]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1cccc(Br)c1
Reactant: C1=COCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cccc(C2CC=CO2)c1
Temperature: 45 °C
Yield: 38.3 %

Procedure:
Ex-119A: 5-Bromobenzaldehyde (0.5 g, 2.7 mmol) and 2,3-dihydrofuran (0.56 g, 8.1 mmol) were dissolved in dioxane (5.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (0.96 g, 2.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.027 mmol). The solution was immediately heated to 45° C. and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:9) gave 0.18 g (40%) of 3-(2,3-dihydro-furan-2-yl)-benzaldehyde as a clear, colorless oil. 1H-NMR (300 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.62–7.64 (m, 1H), 7.53 (t, 1H, J=7.2 Hz), 6.48 (q, 1H, J=Hz), 5.60 (dd, 1H, J=8.1, 10.8 Hz), 4.98 (q, 1H, J=3.3 Hz), 3.15 (ddt, 1H, J=15.0, 8.1, 2.5 Hz), 2.59 (ddt, 1H, J=15.0, 8.1, 2.5 Hz). MS (EI) m/z=174 ([M]+, 100%). HRMS (EI) Calcd. for C11H10O2: 174.0681. Found: 174.0677.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 1H-pyrrolo[2,3-B]pyridine-3-carbaldehyde (2.0 g, 13.7 mmol) in 20 mL DMF at 0° C. was added NaH (328 mg, 13.7 mmol). The suspension was allowed to stir at 0° C. for 30 min, then [2-(chloromethoxy)ethyl](trimethyl)silane (2.67 mL, 15.1 mmol) was slowly added. The reaction was allowed to warm to ambient temperature and stirred for 16 h. The mixture was concentrated and partitioned between saturated NaHCO3 and CH2Cl2. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The crude solid was triturated with CH2Cl2 and filtered. The filtrate was concentrated and purified by silica gel chromatography (0-25% ethylacetate/hexanes) to give 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (66%). LCMS [M+H]+=277.1.