Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C=O)([O-:3])=[O:2].C1[C:17]([OH:18])=CC=CC=1C.C=O.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH:17]=[O:18])([O-:3])=[O:2]
Reactant: Cc1cccc(O)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: C=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
190.0 g of water-moist m-nitrobenzaldehyde (containing 163.0 g of crude nitrobenzaldehyde of the composition: 1.5% by weight of o-isomer; 2.3% by weight of p-isomer; 96.2% by weight of m-isomer) were suspended in 445 g of water and 20.0 g of an emulsifier, which was prepared by condensation of m-cresol, formaldehyde, sodium sulphite and 2-naphthol-6-sulphonic acid, were added. The suspension was heated to 60° C. and adjusted to pH 10.4 using NaOH. The mixture was subsequently heated to reflux and stirred under reflux for 30 minutes. It was then cooled to 40° C., stirred at 40° C. for 2.5 hours and filtered off with suction. The filtered material was washed with water and freshly filtered with suction. After drying, 141.7 g of m-nitrobenzaldehyde were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH2:21]([NH:23][CH2:24][CH2:25][OH:26])[CH3:22]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][OH:26])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(ethylamino)ethanol were converted to yield 2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-ethyl-amino]-ethanol, MS: 422 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][N:10]([C:21](=[O:23])[CH3:22])[CH2:11]2)=[CH:12][CH:13]=1
Reactant: Brc1ccc(OCC2CNC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(COc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 0.91 mmol) in CH2Cl2 (10 mL) was added triethylamine (276 mg, 2.73 mmol) and acetic anhydride (186 mg, 1.82 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a yellow oil. The crude product was diluted with ethyl acetate (20 ml), washed with 1N HCl followed by saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 1-{3-[(4-bromophenoxy)methyl]azetidin-1-yl}ethanone (233 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.78 (d, 2H), 4.28 (m, 1H), 4.24-4.00 (m, 4H), 3.87 (m, 1H), 3.07 (m, 1H), 1.90 (s, 3H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:20])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of indole-2-carboxylic acid (1 g, 6.21 mmol) in MC (30 ml), oxalyl chloride (1.64 ml, 0.18.62 mmol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (20 ml), to which a solution of ammonium hydroxide in water (7 ml) was dropwise added with cooling in an ice bath. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to give the title compound, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12.[CH3:35][N:36](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12)#[N:36]
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COC(=O)c1ccc2c(c1)c(-c1cc3c(C#N)ccnc3[nH]1)cn2C
Temperature: 140 °C

Procedure:
A mixture of 3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl]-1-methyl-1H-indole-5-carboxylic acid, methyl ester [0.4 g, Reference Example 2(r)], zinc powder (0.05 g), zinc cyanide (0.117 g), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichlroromethane (catalytic) and N,N-dimethylacetamide (8 mL) was heated at 130-150° C. for 5 hours. The reaction mixture was cooled, filtered and the precipitated washed with dimethylformamide (2 mL). The filtrate was diluted with ethyl acetate (120 mL) and the solution extracted with water (2×20 mL). The combined organic layer was evaporated and the residue subjected to flash column chromatography on silica gel eluting with a mixture of heptane and ethyl acetate (7:3 v/v) moving to neat ethyl acetate to give the title compound (0.12 g) as a bright yellow solid. MS: 331(MH+). HPLC(Method C): RT=4.01 minutes.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47]OC.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:59])[CH:55]=[CH:56][C:57]=1[I:58]>>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47][NH:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:59])[CH:55]=[CH:56][C:57]=1[I:58]
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Reactant: NCc1cc(O)ccc1I
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNCc1cc(O)ccc1I
Yield: 77 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (400 mg, 1.5 mmol) and 3-Aminomethyl-4-iodo-phenol (400 mg, 1.61 mmol) in 77% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])C1C=CC=CC=1>CO.[Pd]>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][O:12][C:11]1[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=1[OH:9]
Reactant: CN(C)CCOc1ccccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCOc1ccccc1O
Reaction time: 2 h
Yield: 107 %

Procedure:
To a solution of N-{2-[2-(benzyloxy)phenoxy]ethyl}-N,N-dimethylamine (from Step 1; 7.60 g, 28.0 mmol) in MeOH (80 mL) was added 10% Pd/C (0.8 g) and the mixture was hydrogenated at 70 psi and room temperature for 2 h. The reaction mixture was filtered through a pad of Celite® and silica. The solvent was then removed under reduced pressure to give 5.43 g (quantitative yield) of the title compound as off-white crystals: mp 220° C. HRMS m/z calcd for C10H15NO2 (M)+ 181.1103. Found 181.1105. *The corresponding hydrochloride salt has been reported in Bull. Soc. Chim. Fr. 1935, 1737–1741.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:10]N.C1COCC1.O1CCOCC1>ClCCl>[NH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: NN
Reactant: c1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1n[nH]c2ccccc12

Procedure:
Indazole (XV) is treated with hydrazine in an organic solvent such as THF, dioxane or dichloromethane, at a temperature in the range of about 0° C. to about 25° C., to yield the corresponding indazole (IV).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:33]([O:35][CH3:36])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].O.C(O)C(F)(F)F.C(=O)=O>CO>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:33]([O:35][CH3:36])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C=O
Solvent: OCC(F)(F)F
Solvent: O
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
8 g of Z-Ile-His-Lys(Boc)-OMe are suspended in a mixture of 80 ml of MeOH, 8 ml of H2O and 80 ml of trifluoroethanol, and hydrogenated with 800 mg of Pd-on-carbon (10% Pd) with CO2 -absorption until saturation, the initially undissolved material being dissolved. The catalyst is filtered off, the filtrate is concentrated to dryness and the resinous residue is crystallised from acetonitrile, yielding H-Ile-His-Lys(Boc)-OMe in the form of needles having a melting point of 129°-130°; Rf (I)=0.12; Rf (B)=0.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[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][C:32]=2[F:40])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:44](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO.C(Cl)Cl>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:41])[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])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([F:40])[CH:33]=1)(=[O:37])[NH2:44]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.03 h

Procedure:
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-fluorobenzoic acid (70 mg, 116 μmol, Eq: 1.00) was combined with CH2Cl2 (5.43 ml) to give a suspension. DIPEA (18.0 mg, 24.3 μl, 139 μmol, Eq: 1.2) and HATU (48.4 mg, 127 μmol, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (290 μl, 579 μmol, Eq: 5) in Methanol was added. The reaction mixture was stirred for overnight.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:19][CH2:18][C:12]2([CH2:16][N:15](C)[CH2:14][CH2:13]2)[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH3:3][N:10]1[CH2:19][CH2:18][C:12]2([CH2:13][CH2:14][NH:15][CH2:16]2)[CH2:11]1
Reactant: CN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCC2(CCNC2)C1

Procedure:
A solution of 7-benzyl-2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 150 ml of methanol with 1.0 g 20% palladium on carbon catalyst was hydrogenated at 4.5×105Pa for two days. After filtration, the filtrate was concentrated to a thick syrup which crystallized on addition of acetonitrile to give 11.50 g of the title compound, softened at 164° C. and melted at 168°-170° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].O[C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[N:14][CH:15]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[N:14][CH:15]=1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC12CCC(c3ccc(-c4ncc(O)cn4)cc3)(CC1)CC2
Reactant: CCC/C=C/C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g, 0.9 mmol), 1-[4-(5-hydroxypyrimidin-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.9 mmol), 4-(dimethylamino)pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester (0.15 g, 45%).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.CO>C(OCC)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:11][CH:12]=1)#[N:17]
Reactant: COC(=O)CCCOc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(OCCCCO)cc1
Yield: 46 %

Procedure:
LiBH4 (1.5 g; 71.1 mmol) was added to a stirred solution of 4-(4-cyanophenoxy)butyric acid methyl ester (9.63 g; 47.4 mmol; from step (b) above), MeOH (2.87 mL; 71.1 mmol) and diethyl ether (158 mL) and the reaction mixture was refluxed overnight. The ether phase was collected and the residue was extracted with diethyl ether (3×50 mL). The combined organic phase was dried, concentrated and purified using column chromatography (EtOAc:hexane; 1:3) to give the sub-title compound (3.82 g; 21.8 mmol).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CCN2CCC(n3ccc4ccc(Br)cc43)CC2)cc1
Yield: 482.4 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.1 g) was dissolved in chloroform (27 ml). After adding manganese dioxide (2.75 g), the resultant mixture was heated under reflux for 4 hr. Then manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (0.480 g) as a yellow oil (yield: 96.5%).
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][C:9]=2[CH3:23])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][C:9]=2[CH3:23])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2n(c1C(=O)c1cccs1)CCCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc2n(c1C(=O)c1cccs1)CCCC2C(=O)O

Procedure:
A solution of 900 mg. of isopropyl 3-(2-thenoyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 15 ml. of methanol is treated with a solution of 125 g. of potassium carbonate in 10 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 50 ml. of water, cooled to 0° and made acidic with 10% aqueous hydrochloric acid. The resultant mixture is extracted with ethyl acetate (3×50 ml.). The extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 3-(2-thenoyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid (XIIa, R=CH3, M=H, X=S, n=1).
Reaction SMILES: S(Cl)(Cl)(=O)=O.C1C2C(=CC=CC=2)C=CC=1.[C:16]1([CH2:26][O:27][CH2:28]SC)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CS[Cl:33]>ClCCl>[Cl:33][CH2:28][O:27][CH2:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSCOCc1cccc2ccccc12
Reactant: CSCl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccc2ccccc2c1
Product: ClCOCc1cccc2ccccc12

Procedure:
1-Chloromethyloxymethyl)naphthalene Sulfuryl chloride (12 mmol) in dry dichloromethane (20 mmol) was added dropwise with stirring to a solution of methylthiomethyl 1-naphthylmethyl ether (12 mmol) in dry dichloromethane (40 ml) at room temperature. After stirring for 30 min the solvent and methanesulfenyl chloride formed in the reaction were distilled off at reduced pressure. The residual material was used for alkylation without further purification. 1H NMR (CDCl3): δ5.13 (CH2), 5.47 (CH2Cl), 7.2-8.3 (Naph).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13](B(OCCCC)OCCCC)=[CH2:14].[F-].[Cs+]>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.COCCOC.CO>[CH3:8][C:6]1[CH:7]=[C:2]([CH:13]=[CH2:14])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: C=Cc1cc(C)c([N+](=O)[O-])cc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (1.15 g, 5.0 mmol), dibutyl vinylboronate (1.16 g, 6.3 mmol), Pd(PPh3)4(289 mg, 0.25 mmol), CsF (2.28 g, 15 mmol) and a mixed solvent (1,2-dimethoxyethane/MeOH=2:1, 15 mL). The mixture was degassed and sealed with N2. The reaction vessel was then heated to 130° C. in a microwave reactor for 15 min. After opening the reaction vessel, the mixture was poured into saturated NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (MgSO4). After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-30% EtOAc in hexanes gradient) to provide 1,4-dimethyl-2-nitro-5-vinylbenzene as needlelike crystals; ESMS m/z 178.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16]Br)[CH:9]=3.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][O:21][C:18](=[O:20])[CH3:19])[CH:9]=3
Reactant: CC(=O)[O-]
Reactant: BrCc1ccc2c(ccc3ccc(Br)cc32)c1
Agent: [K+]
Solvent: CCOCC
Product: CC(=O)OCc1ccc2c(ccc3ccc(Br)cc32)c1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of 3-bromo-7-(bromomethyl)-phenanthrene (2.249 g, 6.425 mmol) and potassium acetate (1.26 g, 12.8 mmol) in 60 ml of DMf was heated at 80° C. for 7 hours. After cooling to RT, the reaction mixture was diluted with ethyl ether, washed with water and brine, dried (MgSO4) and evaporated to give 2.042 g (97%) of the title compound as a white solid which was used in the following reaction without purification.
Reaction SMILES: I[C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])(C)(C)C.[CH2:19]([C:21]1[C:22]([NH:30][C@H:31]2[C@@H:35]([O:36][CH2:37][CH3:38])[CH2:34][N:33]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:32]2)=[N:23][C:24]([CH2:28][CH3:29])=[C:25](I)[N:26]=1)[CH3:20].C(=O)(O)[O-].[Na+]>C1COCC1.[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>[CH2:19]([C:21]1[C:22]([NH:30][C@H:31]2[C@@H:35]([O:36][CH2:37][CH3:38])[CH2:34][N:33]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:40])[CH2:32]2)=[N:23][C:24]([CH2:28][CH3:29])=[C:25]([C:2]2[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[N:26]=1)[CH3:20]
Reactant: COc1ccc(I)c(C(F)(F)F)n1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(I)nc1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
To a solution of 3-iodo-6-methoxy-2-(trifluoromethyl)pyridine (162 mg, 3 eq.) and Zinc chloride (0.5 M THF, 9 eq.) in THF (2.67 ml) under N2 at −78° C. was added t-butyl lithium (9 eq.). After 5 min, the reaction mixture was warmed to ambient temperature and cannula'd into a flask containing benzyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (120 mg) and palladium tetrakis (31 mg). The reaction mixture was heated at reflux for 16 h, poured into saturated sodium bicarbonate (50 ml), extracted 3×50 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Purification via MPLC chromatography eluting with 20–45% ethyl acetate/heptane afforded the title compound as an amorphous solid (63 mg, 53%):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH:17]1([CH2:20][C:21]2[C:26]([CH2:27]O)=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[N:22]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][C:26]3[C:21]([CH2:20][CH:17]4[CH2:19][CH2:18]4)=[N:22][C:23]([C:33]4[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)=[CH:24][C:25]=3[C:29]([F:30])([F:32])[F:31])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3CC3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.