Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:22][C:23]([F:27])([F:26])[S:24]Cl>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[S:24][C:23]([F:27])([F:26])[F:22])=[CH:6][CH:5]=1
Reactant: FC(F)(F)SCl
Reactant: FC(F)(F)Oc1ccc2cn[nH]c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc2cnn(SC(F)(F)F)c2c1

Procedure:
20.2 g (0.1 mole) of 6-trifluoromethoxyindazole and 10.1 g (0.1 mole) of triethylamine in 125 ml of toluene are heated to 80° to 85° C., and 13.6 g (0.1 mole) of trifluoromethanesulphenyl chloride are then passed in the course of one hour and the mixture is stirred for a further hour at this temperature. After cooling, the precipitated triethylamine hydrochloride is filtered off with suction and rinsed with toluene. The filtrate, combined with the wash liquor, is washed twice with water. After drying (MgSO4) the volatile constituents are removed by distillation under a water pump vacuum. The oily crude product is purified by distillation under an oil pump vacuum. Boiling point 62°/0.05 mbar. Yield: 16.2 g (46% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28]Cl)=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][I:32])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCI)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate (0.5 g, 1.11 mmole). In dry acetone (10 ml) was added sodium iodide (0.75 g, 5.0 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 0.53 g=88%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1CCCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1(C)CCCC1=O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of methyl 2-oxocyclopentanecarboxylate (67 g, 0.47 mol), K2CO3 (163 g, 1.18 mol) and MeI (167 g, 1.18 mol) in acetone (500 mL) was heated under reflux for 12 h. The mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in EtOAc (800 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 1-methyl-2-oxocyclopentanecarboxylate (60.5 g, 82% yield).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:17][C:11]=3[N:10]=2)C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:17][C:11]=2[N:10]=1
Reactant: O=C1CCC(c2ccc3[nH]c(CCCN4C(=O)c5ccccc5C4=O)nc3c2)=NN1
Agent: NN
Solvent: O
Product: NCCCc1nc2cc(C3=NNC(=O)CC3)ccc2[nH]1
Yield: 34.6 %

Procedure:
Prepared by a method analogous to that of Example 1d) from 3.3 g (8.2 mmol) of 6-[2-(3-phthalimidopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone and 2.0 ml (41.1 mmol) of hydrazine hydrate. 0.77 g (35%) of a colorless solid melting at 247° to 249° C. (decomp.) are obtained after chromatographic purification on silica gel with methanol/conc. ammonia (95:5) as solvent, concentration of the main fraction by evaporation under vacuum and crystallization of the residue from ethanol.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]=[O:12]>CO>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]([OH:12])[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3]
Reactant: COC(C=O)OC
Reactant: C=CC(=O)OCC
Solvent: CO
Product: C=C(C(=O)OCC)C(O)C(OC)OC

Procedure:
118 mmoles ethyl acrylate and 10 g (86.5 mmoles) of 90% by weight dimethoxyethanal in methanol were reacted using the method of example 1 to form 4,4-dimethoxy-2-ethoxycarbonyl-3-hydroxy-1-butene as a liquid which distilled at 108° C. under 0.3 mbar.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][O:15][CH3:14])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: COCCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
In 30 ml of 95% ethanol were dissolved 1.5 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.85 g of 4-(2-methoxyethoxy)benzyl bromide, and then 0.48 g of anhydrous sodium carbonate was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting solid was recrystallized from n-hexane-benzene to obtain 1.64 g of the aimed compound, m.p. 105.6°~107.3° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[Br:20][C:21]1[CH:22]=[C:23]([NH2:28])[CH:24]=[N:25][C:26]=1[CH3:27].C(N(CC)CC)C>ClCCl.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:28][C:23]4[CH:24]=[N:25][C:26]([CH3:27])=[C:21]([Br:20])[CH:22]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ncc(N)cc1Br
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.76 g, 13.4 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (3.0 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 10 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 10 mL of anhydrous dichloromethane. This solution was then slowly added to a solution of 5-bromo-6-methylpyridin-3-amine (2.50 g, 13.4 mmol) in 10 mL of anhydrous dichloromethane containing triethylamine (5.64 mL, 40.2 mmol). The resulting mixture was allowed to stir for 10 minutes at room temperature. The crude product was then washed three times with a saturated aqueous solution of sodium bicarbonate, followed by two washes with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, evaporated to dryness, and the resulting yellow powder (3.62 g, 9.65 mmol, 72.0%) was used without further purification. ESI-MS m/z calc. 374.0, found; 375.1 (M+1)+ Retention time 2.30 minutes. 1H NMR (400 MHz, CD3CN) δ 8.38 (d, J=2.2 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.80-7.60 (m, 1H), 7.08-6.95 (s, 2H), 6.89 (dd, J=1.2, 7.3 Hz, 1H), 6.01 (s, 2H), 2.54 (s, 3H), 1.59-1.50 (m, 2H), 1.19-1.09 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH:5]([CH3:8])[NH:4][C:3]1=[O:9].Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[C:13]=1[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:14]1[C:13]([CH3:21])=[C:12]([N:4]2[CH:5]([CH3:8])[C:6](=[O:7])[C:2]([CH3:10])([CH3:1])[C:3]2=[O:9])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC1NC(=O)C(C)(C)C1=O
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1F

Procedure:
Using 3,3,5-trimethylpyrrolidine-2,4-dione (400 mg), 4-bromo-2-fluoro-3-methylbenzonitrile (667 mg), cesium carbonate (1.39 g), tris(dibenzylideneacetone)dipalladium(0) (130 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (246 mg), and in the same manner as in Reference Example 18, the title compound was obtained as colorless crystals (yield: 137 mg, 18%).
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:9]#[N:10]>>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: C#N
Reactant: O=C(O)CC(=O)CCl
Product: N#CC(O)(CCl)CC(=O)O

Procedure:
reacting 3-oxo-4-chlorobutyric acid with HCN in an aqueous system to form 3-cyano-3-hydroxy-4-chlorobutyric acid,
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[F:35][C:34]([C:32]([OH:38])=[O:33])([F:37])[F:36]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 144 %

Procedure:
Boc-L-Ile-D,L-Pip-OBzl (432 mg, 1 mmol) was dissolved in TFA (3 ml) and allowed to stand for 30 minutes under ice cooling. The reaction solution was distilled and dried under reduced pressure to yield H-L-Ile-D,L-Pip-OBzl TFA (638 mg; yield 144%), which was then dissolved in DMF (5 ml). The solution was mixed with Boc-D-Cha-OH (326 mg, 1.2 mmol) and subsequently mixed with HOBt H2O (230 mg, 1.5 mmol, 1.5 equivalents), Et3N (0.52 ml, 3.7 mmol, 3.7 equivalents) and BOP (663 mg, 1.5 mmol, 1.5 equivalents) under ice cooling, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated, extracted with ethyl acetate (100 ml), and washed twice with 10% citric acid, 4% NaHCO3 and brine, respectively. After drying over magnesium sulfate, ethyl acetate was distilled off. The residue was vacuum dried and purified by flash chromatography (2.4×14 cm) with CHCl3/MeOH (99:1) to yield Boc-D-Cha-L-Ile-D,L-Pip-OBzl (565 mg, 0.96 mmol; yield 96%) as a foam.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[CH2:19][C:20]2([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[O:14])=[CH:8][CH:7]=1)(=O)C>N.CO>[CH:33]1([CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=2)[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[CH2:19][C:20]2([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22][CH2:21]2)=[O:14])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C2CCCC2)cc1
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(CO)cc3)C3CCCC3)c2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
12.50 g (24.72 mmol) of (+/−)-tert-butyl 1-[3-({[4-(acetoxymethyl)phenyl](cyclopentyl)acetyl}-amino)benzyl]cyclopropanecarboxylate were dissolved in 228 ml of a 2 M solution of ammonia in methanol and stirred at 30° C. for 2 h, then at 40° C. for 2 h and finally at RT overnight. The solution was then concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→2:1). This gave 11.88 g (96.5% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2cnc(OCc3ccc(C(C)=O)cc3)s2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cnc(OCc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-yloxymethyl]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-yloxymethyl]acetophenone oxime in 57% yield, m.p. 107°-109° C.;
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CN1C(=O)CCC1>[CH:22]1([NH:25][C:12]2[N:11]=[C:10]([NH:9][C@@H:4]3[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]3)[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:24][CH2:23]1
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC3CC3)ncc2C#N)C[C@H]1O
Temperature: 80 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To a solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (362 mg, 1.166 mmol; synthesis described herein) in NMP (5.832 mL), was added cyclopropanamine (0.485 mL, 7.00 mmol). The reaction was stirred at 80° C. for 5 h in a sealed vessel and then allowed to cool to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to an oil that was purified by silica gel chromatography (0-60% ethyl acetate/hexane) to afford 2-(cyclopropylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (265 mg, 0.922 mmol, 79% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-8.32 (m, 3H), 4.54 (d, J=5.08 Hz, 1H), 3.85-4.13 (m, 1H), 2.80-3.03 (m, 1H), 2.58-2.75 (m, 1H), 1.50-2.08 (m, 3H), 1.03-1.42 (m, 3H), 0.88 (d, J=6.25 Hz, 4H), 0.29-0.68 (m, 4H). MS (ESI) m/z 288.1 [M+1]+.
Reaction SMILES: C(N)C#C.ClC=CC(Cl)Cl.[CH2:11]([NH:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:12]#[CH:13].[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>>[CH2:11]([N:14]([CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[C:12]#[CH:13]
Reactant: C#CCNCC=C(Cl)Cl
Reactant: O=C(Cl)C(Cl)Cl
Agent: C#CCN
Agent: ClC=CC(Cl)Cl
Product: C#CCN(CC=C(Cl)Cl)C(=O)C(Cl)Cl

Procedure:
From propargylamine and 1,3,3-trichloropropene, proceeding as in Example 1, there was prepared N-propargyl-N-(3,3-dichloroallyl)amine: b.p.15 mm =88°-91° C., from which, by reaction with dichloroacetyl chloride, there was obtained N-propargyl-N-(3,3-dichloroallyl)dichloroacetamide, (Applicants' Mark 8341), a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14]C2CCCCO2)=[CH:12][C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[C:3]=1[CH3:21].[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:6]1[C:5]2[CH:12]=[C:13]([OH:14])[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=2[O:8][C:7]=1[C:9](=[O:11])[CH3:10]
Reactant: BrBr
Reactant: CC(=O)c1cc2cc(OC3CCCCO3)c(C)c(C)c2o1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1oc2c(C)c(C)c(O)cc2c1Br
Reaction time: 1 h

Procedure:
To a solution of 1-[6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-yl]-ethanone (200 mg) in chloroform (20 mL) was added bromine (120 mg). After 1 h, the solution was washed with water and dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10% hexane in DCM to give 1-(3-Bromo-5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.38 (s, 1H), 5.55 (s, 1H, OH), 2.60, 2.50, 2.31 (3s, 9H) ppm. MS (m/z): 283, 285 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1.C1(N)CCCCC1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[C:6]=1[CH3:14]
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1c(C)n(-c2ccc(Cl)cc2)c2ncccc12
Temperature: 160 °C

Procedure:
A mixture of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (100 mg, 0.49 mmol), 1-chloro-4-iodo-benzene (117 mg, 0.49 mmol), CuI (5 mg, 0.03 mmol), cyclohexane-1,2-diamine (6 μL, 0.05 mmol), potassium phosphate (218 mg, 1.0 mmol) and 1,4-dioxane (0.5 mL) is heated at 160° C. for 140 minutes. The reaction is cooled, diluted with EtOAc, filtered through silica and evaporated to dryness. The residue is purified by flash column chromatography (5:1 iso-hexane/EtOAc elution) to furnish [1-(4-chloro-phenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=315.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[C:10]=1[I:12])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(O)cc(C(=O)O)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(O)c1I
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a solution of 3-amino-5-hydroxy-benzoic acid (0.33 g, 2.16 mmol, 1.0 equiv; [CAS RN 76045-71-1]) in methanol (18 mL) at 0° C. was added within 10 min N-iodo succinimide (0.58 g, 2.59 mmol, 1.2 equiv), dissolved in methanol (3 mL). After stirring for 15 min, the reaction mixture was poured on ice and partly decolorized by addition of a 5% solution of sodium thiosulfate. The solution was extracted with ethyl acetate (3×50 mL), the combined organic phases dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate/methanol (9:1) providing 0.21 g (35%) of the title compound. 1H NMR (300 MHz, DMSO): δ 5.25 (br s, 2H), 6.61 (d, J=1.9 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H), 10.16 (br s, 1H), 12.58 (br s, 1H). MS (ISP): 280.0 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]1([CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.Cl.[N+:32]([CH3:35])([O-:34])=[O:33]>>[N+:32]([CH2:35][CH:8]([Si:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])([O-:34])=[O:33]
Reactant: C[Si]1(C=CC(=O)OCc2ccccc2)CCCCC1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si]1(C(CC(=O)OCc2ccccc2)C[N+](=O)[O-])CCCCC1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of benzyl 3-(1-methyl-1-silacyclohexan-1-yl)acrylate (1.940 g, 7.08 mmol) in nitromethane (5 ml) was cooled on ice, and added with DBU (0.26 ml, 1.74 mmol), and the mixture was stirred for 30 minutes, and further stirred at room temperature for 17 hours. The reaction mixture was added with aqueous hydrochloric acid (1 N), the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate, and then treated in a conventional manner. The residue was purified by silica gel column chromatography [hexane/ethyl acetate (14:1)] to obtain benzyl 4-nitro-3-(1-methyl-1-silacyclohexan-1-yl)butanoate (1.711 g, 72%) mentioned in the title as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH:3]=[CH2:4].[Sn](Cl)(Cl)(Cl)[Cl:16]>O>[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:16])[C:7]=1[NH2:12])[CH:3]=[CH2:4]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: C=CCNc1ccncc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: C=CCNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
35% Hydrochloric acid (55 mL) was added to allyl(3-nitropyridin-4-yl) amine (3.02 g) and this was heated to 90° C. Tin chloride (19.1 g) was added, and this was reacted at 90° C. for 30 minutes. The reaction solution was cooled on iced water, and 250 mL of iced water was added. The reaction solution was concentrated under reduced pressure, and then a saturated solution of ammonia-methanol (250 mL) was added, and this was stirred for 20 hours. Ethyl acetate (750 mL) was then added, and this was filtered through celite, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted by ethyl acetate-hexane (1:1) gave the title compound (2.88 g).