Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][O:10][CH3:11])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>O1CCCC1.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([O:10][CH3:11])[S:22]([CH3:25])(=[O:24])=[O:23])=[N:6][CH:7]=1
Reactant: CONCc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CON(Cc1ccc(Br)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-ylmethyl)-O-methyl-hydroxylamine (0.6 g, 2.765 mmol) in tetrahydrofuran (10 mL) is added sodium bis(trimethylsilyl)-amide (0.6 g, 3.318 mmol) and mesyl chloride (0.37 g, 3.318 mmol) at 0° C. The reaction mixture is stirred at room temperature for 16 hours. Reaction mixture diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by flash chromatography using 20% ethyl acetate in hexane as an eluent to afford the title compound (0.3 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.47 (s, 3H), 4.40 (s, 2H), 7.50 (d, J=8.28 Hz, 1H), 8.09-8.12 (dd, J1=2.8 Hz, J2=8.4 Hz, 1H), 8.71 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=297.1.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18]Cl)[CH:12]=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[Cl:3][C:4]1[CH:14]=[C:13]([N:15]2[CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2=[O:22])[CH:12]=[CH:11][C:5]=1[C:6](=[O:7])[N:8]([CH3:10])[CH3:9]
Reactant: CN(C)C(=O)c1ccc(NC(=O)C(C)(C)CCl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(N2CC(C)(C)C2=O)cc1Cl
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A solution of sodium hydroxide (4.00 g) and tetrabutylammonium bromide (0.10 g) in water (10 ml) was added to a suspension of 2-chloro-4-(3'-chloro-2',2'-dimethylpropionamido)-N,N-dimethylbenzamide (1.00 g) in methylene chloride (10 ml) and the two-phase system stirred at room temperature for I hour. Water (10 ml) and methylene chloride (10 ml) were then added and the whole methylene chloride layer washed with brine, dried and evaporated to give a pale yellow solid. This was recrystallised from ethyl acetate/hexane to give 1-[3'-chloro-4'-(N,N-dimethylcarbamoyl)phenyl]-3,3-dimethylazetidin-2-one as a white crystalline solid (0.516 g), m.p. 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]=2[OH:25])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]OS(OC)(=O)=O.O>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([O:25][CH3:30])[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(OC)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (537 mg, 1.37 mmole) is added to a suspension of 70 mg of 50% sodium hydride (1.46 mmole prewashed with hexanes) in 5 ml of dry dimethylformamide (DMF) under nitrogen. After gas ceased to evolve, 150 μl of dimethylsulfate (1.57 mmole) is added all at once. The resulting yellow-orange solution is stirred for an additional 10 minutes before it is poured into 100 ml of water to precipitate the crude product. The mixture is stirred well followed by filtration. The collected residue is washed with water and dried in vacuo to afford 505 mg of crude ethyl-5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-methoxy-1-methylpyrrole-2-acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>O1CCCC1.CCCCCC.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromoanisole (18.7 g, 0.1 mol) in anhydrous tetrahydrofuran (200 mL) at -78° C. was added a solution of n-BuLi (2.5M solution, 40 mL) in hexane. After stirring for 30 minutes, a solution of zinc chloride (1M solution, 100 mL) in ether was added. After the mixture was stirred for one hour at -78° C., Pd(Ph3P)4 (0.85 g, 0.73 mmol) and 2-bromobenzonitrile (18.2 g, 0.1 mol) were added. The reaction mixture was stirred at room temperature overnight, and then was concentrated in vacuo. The residue was partitioned between ethyl acetate (400 mL) and 1N hydrochloric acid (100 mL). The organic solution was washed with brine and dried over magnesium sulfate. Concentration in vacuo gave a crude intermediate 4'-methoxy[1,1'-biphenyl]-2-carbonitrile, which was directly used for the next step (the compound can be triturated with ether to obtain a pure solid product). To a solution of the crude intermediate in methylene chloride (150 mL) at -78° C. was added boron tribromide (1M solution, 200 mL) in methylene chloride. After the addition, the resulting solution was stirred at room temperature overnight. The reaction was quenched by adding very slowly methanol (100 mL) at -78° C. The mixture was then poured into ice water. Ethyl acetate (300 mL) was added to the aqueous mixture, the organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo gave a solid, which was triturated with ether to obtain the title compound (11.5 g, 59% overall). If needed, the product can also be purified by silica gel column eluting with toluene/ethyl acetate (4:1); m.p. 177-178° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C(Cl)(Cl)Cl.O1CCCC1.[O-2].[O-2].[Mn+4]>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Yield: 72.2 %

Procedure:
A stirred solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (3.5 g) in chloroform (150 mL) and tetrahydrofuran (300 mL) was treated with manganese dioxide (7.8 g) for 18 hours and was filtered and evaporated to give a white solid (2.5 g).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH:14][CH2:15][CH2:16][CH3:17])C.[OH-].[K+].Cl>CO.C(OCC)(=O)C>[CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][C:4]([OH:18])=[O:3])=[CH:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCC=Cc1ccccc1C=CC(=O)OCC
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)O
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC=Cc1ccccc1C=CC(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-3-[2-((Z)-1-pentenyl)phenyl]propenoic acid ethyl ester (2 g) in 20% aqueous methanol was added potassium hydroxide (2.3 g). The mixture was stirred for 2 hours at 60° C., adjusted to pH 1 with hydrochloric acid and extracted with ethyl acetate. After the extract was dried over magnesium sulfate and filtered, the solvent was evaporated. The residue was dissolved in a mixture of n-hexane and ethyl acetate (4:1). The solution was added to dicyclohexylamine (1.63 ml) to give crystals. The crystals were dissolved in ethyl acetate and washed with 1N sulfuric acid. The solution was dried over magnesium sulfate, filtered and evaporated to give (E)-3-[2-((Z)-1-pentenyl)phenyl]propenoic acid (0.92 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(Cl)nc3)sc2c1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc2nc(-c3ccc(Sc4ccccc4)nc3)sc2c1O
Temperature: 100 °C

Procedure:
A suspension of 2-(6-chloro-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester, example 92(c)(0.25 g, 0.75 mmol) and triethylamine (0.21 mL, 1.49 mmol) in thiophenol was heated at 100° C. overnight. 100 mL of chloroform was added. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to produce 49.0 mg of a light yellow solid. MS: (+) m/z 410.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH:13][CH:14]([CH2:18][CH2:19]Br)[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH:13][CH:14]1[CH2:18][CH2:19][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:16][CH2:15]1
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Reactant: OC(CCBr)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 6-aminocarbostyril, 1.6 g (0.01 mole), crude bromopentanes from step c, 3.1 g, anhydrous sodium carbonate, 2.0 g (0.020 mole), and dimethylformamide, 15 mL, was heated for 4.5 hours at 100° C. with occasional stirring. The mixture was then cooled and diluted with water, 150 mL, to give a pasty precipitate which was filtered off and washed with water to give a sticky solid (2.9 g). The solid was taken up in hot methanol and the insoluble material filtered off (0.6 g, mp 270°-280° C.). Further treatment with hot methanol gave 0.4 g of the desired product, mp 280°-283° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[C@@H:17]([N:18](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:18][C@H:17]1[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12][C@H:11]1[CH2:10][CH2:9][OH:8]
Reactant: O=C1Nc2cc(F)ccc2O[C@@H](CCOCc2ccccc2)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1C(=O)Nc2cc(F)ccc2O[C@H]1CCO
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield by hydrogenation of (6S,7R)-6-(2-benzyloxy-ethyl)-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 241.3 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:6]([CH:7]=[CH:8][CH:9]=[C:10]1[C:16]([OH:18])=O)=[N:5]2.[NH2:19][CH2:20][CH2:21][N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1>S(Cl)(Cl)=O.ClCCl>[CH2:33]([N:22]([CH2:21][CH2:20][NH:19][C:16]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH:7]=[CH:8][CH:9]=1)=[O:18])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:34]
Reactant: O=C(O)c1cccc2nc3cc(Br)ccc3nc12
Reactant: CCN(CCN)CCOc1cccnc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CCNC(=O)c1cccc2nc3cc(Br)ccc3nc12)CCOc1cccnc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A solution of 7-bromophenazine-1-carboxylic acid (81) (333 mg, 1.10 mmol) (Madelmont, J. C.; Chezal, J. M.: Moins, N.; Teulade, J. C.; Chavignon, O. Labelled analogues of halobenzamides as radiopharmaceuticals, WO 2008/012782A3) in thionyl chloride (8 mL) was refluxed, under argon, for 1 h. After cooling to room temperature, the solvent was evaporated under reduce pressure and the residue was dissolved in anhydrous toluene (5 mL). The solvent was evaporated under vacuum and the residue was dissolved in anhydrous dichloromethane (11 mL). A solution of compound 5 (300 mg, 1.32 mmol) in anhydrous dichloromethane (5 mL) was added, at 0° C. and the mixture was then stirred at room temperature for 24 h. The solvent was evaporated under reduce pressure and the residue was chromatographed (Al2O3, AcOEt) to give compound 82 (537 mg, 1.05 mmol) as a yellow oil. Yield 95%; Rf (Al2O3, AcOEt) 0.69; IR (CCl4) ν 1190, 1249, 1283, 1466, 1517, 1663, 2800-3000, 3250-3350 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 3H, J=7.1 Hz), 2.80 (q, 2H, J=7.1 Hz), 2.86 (t, 2H, J=6.0 Hz), 3.00 (t, 2H, J=5.5 Hz), 3.70 (q, 2H, J=6.0 Hz), 4.04 (t, 2H, J=5.5 Hz), 6.75 (ddd, 1H, 5JH-F=0.8 Hz, J=4.8, 7.9 Hz), 6.93 (ddd, 1H, 4JH-F=10.1 Hz, J=1.5, 7.9 Hz), 7.45 (td, 1H, 4JH-F=1.5 Hz, J=1.5, 4.8 Hz), 7.71 (dd, 1H, J=2.0, 9.2 Hz), 7.82 (dd, 1H, J=7.1, 8.7 Hz), 7.89 (d, 1H, J=9.2 Hz), 8.15 (dd, 1H, J=1.5, 8.7 Hz), 8.23 (d, 1H, J=2.0 Hz), 8.84 (dd, 1H, J=1.5, 7.1 Hz), 10.79 (m, 1H); ESI-MS m/z 512.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH3:34])[CH:27]=[C:28]([O:32]C)[C:29]=1[O:30][CH3:31]>ClCCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:27]1[C:28]([OH:32])=[C:29]([O:30][CH3:31])[C:24]([O:23][CH3:22])=[CH:25][C:26]=1[CH3:34])=[O:16])(=[O:3])[CH3:2]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CC(=O)OCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCOC(C)=O)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution (150 ml) of 11-acetoxy-n-undecanoyl chloride (27.6 g) in 1,2-dichloroethane is added aluminum chloride (28 g), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled to 5° C. followed by addition of a solution (50 ml) of 3,4,5-trimethoxytoluene (19.1 g) in 1,2-dichloroethane and the whole mixture is stirred at room temperature for 72 hours. The reaction mixture is then heated to 50°-60° C. and stirred for 30 minutes. After cooling, 300 ml of ice water is added to the reaction mixture and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off to give a light-yellow oil of 6-(11-acetoxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (33 g).
Reaction SMILES: [Si:1]([C:8]#[C:9][CH2:10][N:11]1[C:16]([I:17])=[CH:15][C:14]([CH:18]([OH:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH3:27])[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[Si:37]([CH3:47])([CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:1]([C:8]#[C:9][CH2:10][N:11]1[C:16]([I:17])=[CH:15][C:14]([CH:18]([O:26][Si:37]([CH3:46])([CH3:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH3:27])[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: Cc1c(C(O)Cc2ccccc2)cc(I)n(CC#C[Si](C)(C)C(C)(C)C)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC[Si](C)(C)OC(Cc1ccccc1)c1cc(I)n(CC#C[Si](C)(C)C(C)(C)C)c(=O)c1C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To a solution of 1-[3-(tert -butyldimethylsilanyl)prop-2-ynyl]-4-(1-hydroxy-2-phenylethyl)-6-iodo-3-methyl-1H-pyridin-2-one 4a (60 mg, 0.12 mmol) and 4-dimethylaminopyridine (2 mg, 1.2 μmol) in CH2Cl2 (2 mL) was added NEt3 (49 mg, 66 μL, 0.48 mmol) and chlorodimethyloctylsilane (62 mg, 77 μL, 0.3 mmol). The resulting mixture was stirred for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes-EtOAc 15:1) to afford 5a (41 mg, 51%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ7.32-7.24 (m, 3H), 7.15-7.12 (m, 2H), 7.08 (s, 1H), 5.14 (d, J=17.0, 1H), 5.09 (d, J=17.0, 1H), 4.79 (t, J=6.4 Hz, 1H), 2.79 (d, J=6.4 Hz, 2H), 1.98 (s, 3H), 1.39-1.11 (m, 14H), 0.94 (s, 9H), 0.90-0.87 (m, 3H), 0.10 (s, 6H), −0.17 (s, 3H), −0.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ162.3, 152.0, 137.8, 129.7, 129.1, 128.3, 127.5, 127.2, 126.6, 118.6, 88.4, 44.6, 33.5, 32.0, 29.4, 29.3, 26.1, 23.2, 23.0, 22.7, 17.9, 16.5, 14.2, 12.0, −0.19, −2.05, −4.78.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C1CC=CCC=1>CCO>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@H:13]([CH2:15][OH:14])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A 3 L 3-necked flask equipped with a mechanical stirrer, a reflux condenser, a thermocouple and a heating mantel is charged with EtOH (1500 mL), (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (70.00 g, 0.232 mol), sodium bicarbonate (38.98 g, 0.464 mol) and 1,4-cyclohexadiene (39.56 mL, 0.418 mol). Argon gas is bubbled through the suspension for 5 min, and then the bubbling is discontinued, and palladium (10% on carbon, 4.9 g) is added. The mixture is heated to an internal temperature of 60° C. and stirred at 60° C. for 1 h. The solution is cooled to rt, filtered through a pad of celite and evaporated to dryness. The residue is dissolved in EtOAc (800 mL), and washed with 1 N HCl (2×100 mL) and brine (100 mL), and the volatiles are removed. The title compound (47.33 g, 93%) is obtained as a tan powder. LCMS (Standard Method): 2.23 min, 212 (M+H)+. 1NMR (300 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 4.42 (dd, J=2.1, 11.2 Hz, 1H), 4.32-4.18 (m, 2H), 3.98-3.85 (m, 2H), 2.03 (br s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[O:24][N:23]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
A mixture of 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.19 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.054 g, 0.21 mmol), Cs2CO3 (0.067 g, 0.21 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4) and filtration was followed by concentration. The resulting material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.070 g, 76%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.88 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.44-1.35 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); MS m/z 493 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: COC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](/C=C2\CCSC2=O)[C@H]1C(=O)O
Solvent: CCO
Product: COC(=O)[C@@H]1[C@@H](/C=C2\CCSC2=O)C1(C)C
Yield: 46 %

Procedure:
Using the procedure of Example 17, 4.5 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 2.2 g of methyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+66.5°±1.5° (c=1.2% in ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][CH:19]1[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: CC1CO1
Product: CC(O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
6-Benzyloxyindole (1) (Batcho and Leimgruber, Organic Syntheses, Collective Vol. 7, p. 34 (1990)) is reacted with (±)-propylene oxide and a base in an organic solvent to yield (±)-1-(2-hydroxypropyl)-6-benzyloxyindole (2). Preferably the base is sodium hydride and the solvent is tetrahydrofuran. The temperature is 0° C. to 25° C., preferably about 10° C. Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: Nc1ccc2nc3n(c2c1)CCC3
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2nc3n(c2c1)CCC3
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
8.65 g of 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (2A00) prepared according to W. Reppe Ann. 596 (1955) p. 209 are suspended in 50 cm3 of benzene. To this suspension is added dropwise 6.2 g of acetic anhydride. The mixture is boiled for 15 min and after cooling the precipitated acetyl compound is sucked off. Recrystallization from ethanol yields 7.3 g of 7-acetylamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole. Melting point: 250°-255°C. Two further recrystallizations from ethanol raise the melting point to 260°-262°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:6]([CH:29]=1)[C:7]([N:9]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH2:16][CH:11]2[CH:10]1[CH2:17][N:18]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].O.NN>CO>[NH2:18][CH2:17][CH:10]1[CH:11]2[CH2:16][CH2:15][CH2:14][CH:12]2[CH2:13][N:9]1[C:7]([C:6]1[CH:29]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
A solution of 2-((2-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)octahydrocyclopenta[c]pyrrol-1-yl)methyl)isoindoline-1,3-dione (1 equiv.) and hydrazine monohydrate (4 equiv.) in MeOH (0.5M) was stirred at 70° C. for 3 h and then concentrated in vacuo to a yellow oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (20% MeOH in EtOAc) to firstly remove the impurities and then (2:8:1 MeOH/EtOAc/TEA) to elute the title compound which was concentrated to yield a yellow oil. MS (ESI) 326 (M+H).