Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cccnc1OC1CCC(=O)CC1
Product: Cc1cccnc1OC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C>CCCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@@H:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1CC2(CCC1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C(N[C@H]1CC2(CC[C@@H]1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1

Procedure:
Benzyl [8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate (528 mg) was resolved by HPLC using a chiral AD column (13% isopropanol in heptane) to give benzyl [(7S,8R)-8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate as the slower eluting enantiomer.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.[CH3:23][C:24]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:29])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([N:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])[CH2:36][CH2:35]1)=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)/C=C/c1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A solution of (E)-3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acrylic acid (143 mg, 0.42 mmol), 4-N-Boc-aminopiperidine (Aldrich, 84 mg, 0.42 mmol) in DMF (1.5 mL) was treated with DIPEA (160 μL, 0.92 mmol), and TBTU (160 mg, 0.50 mmol) and the mixture stirred at rt for 2 h. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting first with 30-100% EtOAc/hexanes then 5% MeOH/CH2Cl2 to give the title compound (110 mg, 54%) as a light brown solid. 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.48 (d, 1H, J=5.6 Hz), 8.44 (dd, 1H, J=2.5, 10.5 Hz), 8.18 (d, 1H, J=9.2 Hz), 7.69 (d, 1H, J=15.3 Hz), 7.58 (dd, 1H, J=8.6, 8.6 Hz), 7.50 (d, 1H, J=15.7 Hz), 6.97 (d, 1H, J=5.6 Hz), 6.89 (d, 1H, J=7.6 Hz), 4.31-4.16 (m, 2H), 3.55-3.46 (m, 1H), 3.20-3.14 (m, 1H), 2.83-2.81 (m, 1H), 1.82-1.71 (m, 2H), 1.34-1.18 (m, 2H), 1.37 (s, 9H); MS (ESI+): m/z 431.04 (100) [(M−C4H9)+H]+; m/z 487.10 (90) (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=[O:17])[CH:10]([CH2:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Cl>C(OCC)C>[CH2:18]([N:12]1[CH2:11][CH:10]2[C:16]([OH:17])([CH3:25])[CH:14]([CH2:15][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Mg]Cl
Reactant: O=C1C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Solvent: CCOCC
Product: CC1(O)C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane-9-one (from step (i) above; 2.05 g; 6.4 mmol) in diethyl ether (15 mL) was added to a stirred solution of methyl magnesium chloride (12.8 mmol) in diethyl ether (8 mL) over 80 minutes. The reaction mixture was subsequently stirred for 20 minutes and then quenched with HCl (1 M). The aqueous layer was separated, concentrated and partitioned between EtOAc and NaOH (2 M). The organic layer was separated and subsequently treated with ion exchange resin (Amberlyst IRA 400), the solvent removed and the residue subjected to column chromatography (hexane:EtOAc; 1:1 with NH3 sat. MeOH; gradient 0-32%) to give the sub-tide compound as a diastereoisomeric mixture in a 60% yield.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH2:20].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:13]=2[F:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: Nc1ccc(I)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: -65 °C
Reaction time: 21 h
Yield: 173.7 %

Procedure:
In analogy to GP 1, 1 g of 2,4,6-trifluoro-benzonitrile (6.37 mmol; 1 eq.; commercially available) and 2.26 g 2-fluoro-4-iodo-benzenamine (9.55 mmol, 1.5 eq; commercially available) were dissolved in 100 ml of THF. The mixture was cooled to −65° C.; 2.14 g of potassium tert-butoxide (19.1 mmol, 3 eq; commercially available) were added. The mixture was stirred for 35 min at this temperature and another 21 h at RT. The mixture was stirred into 120 ml of ice water and extracted three times with ethyl acetate (100 ml each). The combined organic layers were washed with brine, dryed over sodium sulfate and concentrated to afford 4.137 g of crude product. Purification was achieved by flash chromatography (hexane/ethyl acetate) to afford 646 mg (27.13% yield; 1.73 mmol) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]#[N:19].C([N:23](C(C)C)CC)(C)C.Cl.NO>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:23])=[NH:19]
Reactant: N#Cc1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: N=C(N)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a suspension of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbonitrile (12.9 g, 46.9 mmol) in ethanol (280 ml) and di-iso-propylethylamine (16.7 ml, 96.0 mmol) was added hydroxylamine hydrochloride (6.8 g, 121.4 mmol). The reaction mixture was warmed to reflux and stirred for 6 h before cooling to room temperature and the solvent removed in vacuo. The solid was dissolved in dichloromethane washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting solid was crystallised from diethyl ether to yield 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxamidine (13.1 g, 42.5 mmol) as an off white solid.
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].C(NCC)C.C([OH:21])C>>[CH3:12][C:2]1([CH3:13])[C:3](=[O:21])[CH:4]=[C:5]([C:7]2[N:8]=[CH:9][S:10][CH:11]=2)[O:6]1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1cscn1
Solvent: CCNCC
Product: CC1(C)OC(c2cscn2)=CC1=O
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(thiazol-4-yl)pent-2-yn-1-one (0.1 g, 0.53 mmol) in ethanol (1 mL) was added diethyl amine (0.057 mL, 0.59 mmol) in EtOH (0.5 mL) dropwise at RT and the reaction mixture was stirred for additional 45 min. Then the EtOH was removed, diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (0.1 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][CH:5]=2.[CH3:18][O-:19].[Na+].[C:21]([OH:24])(=O)C>O1CCCC1>[CH3:18][O:19][C:2]1[C:3](=[O:17])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[O:24][CH3:21])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][CH:5]=2
Reactant: C[O-]
Reactant: CC(=O)O
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)c2c(cccc2[N+](=O)[O-])C1=O
Reaction time: 16 h

Procedure:
A solution of 2,3-dichloro-5-nitro-1,4-naphthoquinone (8, 2.72 g, 10 mmol) in anhydrous tetrahydrofuran (15 ml) is added to a solution of 1 N sodium methoxide (25 ml, 25 mmol) and the resulting solution stored at 22° for 16 hours. Acetic acid (1 ml) is then added, the solution concentrated in vacuo and the residue partitioned between water (50 ml) and chloroform (100 ml). The aqueous phase is further extracted with chloroform (2×50 ml). The combined chloroform extracts are dried with MgSO4 and concentrated in vacuo. The residue is recrystallized from methanol giving 1.99 g (76%) of 10 FIG. 3a (R1 =R2 =OCH3) with mp 156°-157°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C1CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 2 h

Procedure:
The product of Example 1A (6.00 g, 24.7 mmol) was dissolved in 60 mL of ethanol and 10% Pd/C was added (600 mg). The reaction mixture was placed in a Par shaker at 60 psi for 2 h. After this time, the catalyst was filtered, and the solvents evaporated to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.05-1.22 (m, 2 H), 1.22-1.30 (m, 3 H), 1.43-1.59 (m, 2 H), 1.64-1.75 (m, 2 H), 1.86-1.96 (m, 3 H), 2.24 (d, J=6.44 Hz, 2 H), 2.40-2.49 (m, 1 H), 4.15 (q, J=7.35 Hz, 2 H), 7.17-7.23 (m, 3 H), 7.24-7.33 (m, 2 H); MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17]OC)=[O:4].[N:21]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:20][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:33][CH:32]=1)=[O:4]
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(=O)N(C)C)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2c(c1)/C(=C/Nc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Yield: 74.7 %

Procedure:
Prepared from a solution of 70 mg (0.255 mmol) of 4-methoxymethylene-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid dimethylamide and 48.5 mg (0.255 mmol) of 4-piperidin-1-ylmethyl-phenylamine in 1.6 mL of N,N-dimethylformamide (DMF) at 110° C. under N2 as described for example 21. After heating for 0.25 h, the reaction is chilled in ice. The solid product is collected, washed with N,N-dimethylformamide (DMF) and Et2O and dried to give 82.4 mg (74%) of bright yellow crystals: mp 266-267° C. (dec); 1H NMR (DMSO-d6) δ 12.45 (d, 1H, J=9 Hz), 11.40 (s, 1H), 8.95 (d, 1H, J=9 Hz), 8.17 (s, 1H), 8.06 (d, 1H, J=6 Hz), 7.53 (d, 2H, J=9 Hz), 7.32 (d, 2H, J=9 Hz), 7.20 (d, 1H, J=6 Hz), 3.42 (s, 2H), 3.04 (s, 3H), 2.90 (s, 3H), 2.32 (s, 4H), 1.48 (m, 4H), 1.38 (s, 2H); HRMS (ESI) m/e calcd for C25H28N4O3 431.20886, fond 431.20820 (M−H)−1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([CH3:19])=[C:8]([CH3:20])[CH:7]=2.C(N(CC)CC)C.C(Cl)(Cl)Cl>CS(C)=O>[CH3:22][N:4]1[C:3]([CH:2]=[O:1])=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([CH3:20])=[C:9]([CH3:19])[CH:10]=2)[C:5]1=[O:21]
Reactant: Cc1cc2c(-c3ccccc3)c(CO)n(C)c(=O)c2cc1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Cc1cc2c(-c3ccccc3)c(C=O)n(C)c(=O)c2cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution 1,2-dihydro-3-hydroxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline(Reference Example 1) (1.44 g) in DMSO (30 ml) were added triethylamine (2.25 ml) and sulfur trioxide pyridine complex (2.5 g). The mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added chloroform, which was washed with 2N-HCl and water, followed by drying (MgSO4). The solvent was distilled off to leave 1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboaldehyde as colorless crystals (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: CS(=O)(=O)c1cc(CBr)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1Cl
Product: Cl
Temperature: 25 °C
Yield: 27.6 %

Procedure:
(Step 2) A solution of 2-amino-5-chloronicotinamide (484 mg) and 4-(bromomethyl)-1-chloro-2-(methylsulfonyl)benzene obtained in Step 1 (1.2 g) in DMF (10 ml) was stirred at 90° C. for 20 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (160 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[CH:16]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][C:6]=1[O:34][CH3:35].[I-:36].[Na+].C1CCCCC1.C(OCC)(=O)C>C(C(C)=O)C>[I:36][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[CH:16]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][C:6]=1[O:34][CH3:35]
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Yield: 89.3 %

Procedure:
A solution of 2-[6-(2-chloroethoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.660 g, 1,294 μmol) in methyl ethyl ketone (10 ml) is placed in a 50 ml single-necked flask and sodium iodide (0.29 g; 1.941 mmol) is then added. The reaction mixture is refluxed for 16 hours. Analysis by thin layer chromatography (50/50 cyclohexane/ethyl acetate) shows that the reaction has come to an end. After returning to 20° C., the reaction mixture is evaporated under reduced pressure and the residue is taken up in a mixture of water (50 ml) and dichloromethane (50 ml), which is separated by settling out; the organic extract is washed with water (30 ml) and dried over magnesium sulfate. After evaporation, the compound obtained is purified by chromatography on silica gel (cartridge FC-10-Si-BP-Sup, 10 g of silica with a particle size of 15-35 μm, elution being carried out with a 70/30 mixture of cyclohexane/ethyl acetate). The fractions containing the expected: compound are combined and then evaporated under reduced pressure, giving 2-[6-(2-iodoethoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.695 g; 89%) the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13])([CH3:4])([CH3:3])[CH3:2].IC.[C:18](=O)(O)[O-]>CO>[NH:14]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:13][CH3:18].[CH3:18][NH:14][C:12](=[S:13])[NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Reactant: O=C([O-])O
Solvent: CI
Solvent: CO
Product: CNC(=S)NCCCNC(=O)OC(C)(C)C
Product: CSC(=N)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of tert-butyl(3-thioureidopropyl)carbamate (0.29 g, 1.28 mmol) in MeOH (8 mL) was added iodomethane (80 μL, 1.29 mmol). After stirring at rt for 18 h, bicarbonate on polymer support (0.5 g, 3.5 mmol NaCO3/g resin) was added to the reaction mixture. After 30 min, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the desired product along with the N-methylated product, tert-butyl (3-(3-methylthioureido)propyl)carbamate (0.28 g, 87%, 2:1 ratio). The crude residue was used as such in the following step. LCMS: Rt=0.44 min and 0.49 min, m/z=248.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O>[C:36](=[O:37])([O:24][CH2:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26])[O:38][CH3:39]
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(CCOC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 3 h

Procedure:
To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-ol (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 μL, 0.0003 mol) was added. The reaction was stirred for 3 h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z=460.
Reaction SMILES: CCOCC.[Mg+2].[Br-:7].[Br-].S(O[CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22])[CH3:17])(=O)(=O)C>C(OCC)C>[CH2:14]([Br:7])[CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22])[CH3:17]
Reactant: [Br-]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.8 %

Procedure:
To a suspension of magnesium bromide diethyl etherate (25.9 g, 100.3 mmol) in anhydrous diethyl ether (250 mL) under nitrogen at room temperature was added a solution of phytanyl mesylate (18.9 g, 50.2 mmol) in anhydrous diethyl ether (200 mL) dropwise over 15 minutes. The resulting slurry was stirred for 72 hours at room temperature. Upon completion, the reaction mixture was cooled to 0° C. and ice cold water was added dropwise until all solid dissolved and bubbling stopped. Diethyl ether (300 mL) was added, and the organic and aqueous layers separated. The aqueous layer was back-extracted with diethyl ether (200 mL). The combined diethyl ether extracts were dried on MgSO4, filtered, and concentrated. The resulting oil was purified by column chromatography (column 10″L×2″W; eluted with 100% hexanes) to afford the product as a pale yellow oil (16.3 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27]>O>[Cl:1][C:2]1[C:3]([O:12][CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CCCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (100 g), anhydrous potassium carbonate (86.6 g) and dimethylformamide (500 g) was heated at 50° C., and amyl 2-chloroacetate (90.2 g) was dropwise added thereto in 30 minutes, followed by allowing to stand at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water (1500 g) was added thereto, followed by extraction with ethyl acetate (1500 g). The organic layer was separated, washed with water and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)nitrobenzene (Compound (III)) (129 g) as a pale yellow oil. Yield, 77%. b.p., 160 °-165° C./0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][CH2:13][OH:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:15]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH2:12][CH2:13][O:14][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: CC1(CCO)CCc2cc(Cl)ccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(C)CCc3cc(Cl)ccc3O2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
In a nitrogen atmosphere, 11.0 g (0.0495 mol) of 6-chloro-3,4-dihydro-2-(2-hydroxyethyl)-2-methyl-2H-benzopyran was dissolved in 50 ml of pyridine, the solution was cooled to 0° C. and, with vigorous stirring, 11.3 g of p-toluenesulfonyl chloride was added gradually thereto. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 300 ml of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to give 15.3 g of 6-chloro-3,4-dihydro-2-methyl-2-[2-(p-toluenesulfonyloxy)ethyl]-2H-benzopyran.