Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)C.C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(I)c2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(I)c2[nH]ccc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of 7-iodo-5-nitro-2,3-dihydro-1H-indole II (15 g, 51.7 mmol) in ethanol (1200 mL) and isopropanol (20 mL) at 25° C. was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (13.6 g, 59.9 mmol). The resulting solution was warmed to 65° C. and air was bubbled through for 1 h. An additional 0.57 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.8 g, 29.9 mmol) was added and the reaction was stirred at 65° C. for another 2 h before being concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 toluene/ethyl acetate) afforded 7-iodo-5-nitro-1H-indole III (13.07 g, 79%) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.82 (broad s, 1H), 8.59 (d, J=1.83 Hz, 1H), 8.30 (d, J=1.83 Hz, 1H), 7.61 (t, J=2.93 Hz, 1H), 6.90 (dd, J1=1.83 Hz, J2=3.30 Hz, 1H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>O.C(O)(=O)C>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: Nc1ccccc1O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1O
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of potassium cyanate (3.94 g, 48.6 mmol) in water (30 mL) was added during 15 min. to suspension of 2-aminophenol (2.41 g, 22.1 mmol) in 50% aqueous acetic acid (160 mL). The resulting solution was allowed to stand at room temperature overnight and then extracted with ethyl ether (3 times). The combined organic extracts was concentrated to small volume and poured into cold saturated aqueous sodium hydrogen carbonate. The solid was filtered and washed with water to afford the subtitle compound (1.61 g, 47.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+].CO>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][CH:22]([OH:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=c1c(CCC(O)c2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 70.9 %

Procedure:
To a solution of 1-(3-nitrophenyl)-3-[3-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (1.07 g, 2.7 mmol; prepared in Example 17) in dichloromethane (50 ml) was added sodium borohydride, and the mixture was admixed dropwise with methanol (30 ml) gradually while the reaction was monitored by TLC. After completion of the reaction, the mixture was evaporated, admixed with water, and filtered to give a solid which was dried. Recrystallization from DMF yielded 1-(3-nitrophenyl)-3-[3-hydroxy-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (770 mg, 71%; mp 235–236° C./DMF).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:32]B(O)O>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][S:10]4(=[O:15])=[O:14])=[CH:7][C:2]=3[CH3:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3Br)CC2)c(C)c1
Reactant: CB(O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 86 %

Procedure:
Using [2-bromo-4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (120 mg) described in Example 461 and methylboronic acid (42 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (90 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C=O)C.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>[F:35][C:33]1[CH:34]=[C:29]([C:16]#[C:15][CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cc(F)cc(F)c3)CC2)n1
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a suspension of Compound 274c (70 mg, 0.27 mmol), sodium acetate trihydrate (74.2 mg, 0.55 mmol) and 1-bromo-3,5-difluorobenzene (33.5 μl, 0.27 mmol) in 2.05 mL of DMF flushed with nitrogen was added tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.014 mmol) and the reaction mixture was put into a microwave oven (Biotage) at 120° C. for 10 min. Dilution with EtOAc, washing with H2O and drying over Na2SO4 followed by evaporation and purification of the residue by automated flash liquid chromatography (Horizon™-Biotage) (PE-CH2Cl2 6:4) afforded 74 mg (73.7%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]([OH:33])[CH:10]([NH:13][C:14]([CH:16]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH2:17][C:18]([F:23])([F:22])[CH2:19][CH2:20][CH3:21])=[O:15])[CH2:11][CH3:12])[O:6][N:5]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]([C@@H:10]([NH:13][C:14]([C@@H:16]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH2:17][C:18]([F:23])([F:22])[CH2:19][CH2:20][CH3:21])=[O:15])[CH2:11][CH3:12])=[O:33])[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCC(F)(F)CC(NC(=O)N1CCOCC1)C(=O)NC(CC)C(O)c1nc(C2CC2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(=O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (145 mg, 0.31 mmol) in dry dichloromethane (3 mL) under N2 is added Dess-Martin periodinane (15% wt solution in dichloromethane, 1.73 g, 0.061 mmol). The reaction is stirred at room temperature for 2 hr, then quenched with a solution of Na2S2O3 193 mg, 1.22 mmol) in saturated NaHCO3 (30 mL). The aqueous layer is extracted with dichloromethane (2×30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 12 g silica gel, eluted with ethyl acetate: heptane (1:1 then 2:1) to afford the desired ketone (119 mg, 81%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].Br[CH2:11][C:12]([O:14][CH2:15]C)=[O:13].O>O1CCOCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: NCc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CNCc1ccccc1N
Temperature: 25 °C

Procedure:
2-Aminomethyl-phenylamine (1.54 g, 10.1 mmol) and TEA (3.06 ml, 20.2 mmol) are refluxed in 1,4-dioxane. A solution of ethyl bromoacetate (1.12 ml, 10.1 mmol) in 1,4-dioxane (5 ml) is added slowly over 1 hour resulting in a precipitate. The reaction mixture is stirred at reflux for 2 hours. The reaction mixture is cooled to RT, treated with water and extracted with EtOAc, the organic phase is dried over MgSO4, filtered and is concentrated in vacuo. Purification by flash column chromatography on silica, eluting with DCM:MeOH (40:1) affords the title compound; [M+H]+ 195.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]([O:14]C)=[O:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc(Br)cc1)C(=O)O
Yield: 82.6 %

Procedure:
1-bromo-4-(2-methoxycarbonyl-2-methylpropyl)benzene (7.79g) was dissolved in methanol (60 ml) and 2M aqueous sodium hydroxide solution (30 ml) was added. The solution was heated to reflux for 2 hours then cooled. The volume was reduced to ~25 ml by evaporation and the residue extracted with ethyl acetate (15 ml) then acidified with 2M hydrochloric acid and re-extracted with ethyl acetate (3×25 ml). The combined organic extract of the acidified aqueous phase was dried (MgSO4) and evaporated to give 1-bromo-4-(2-carboxy-2-methylpropyl)benzene (6.1 g); 1H NMR (d6 -DMSO): 1.08 (s, 6 H), 2.78 (s, 2 H), 7.11 (m, 2 H), 7.46 (m, 2 H); mass spectrum (CI+) 256 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(N(CC)CC)C>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 36 h
Yield: 58.2 %

Procedure:
6-Aminocaproic acid (26 g, 0.2 mole) was dissolved in dichloromethane (200 mL) by the addition of triethylamine (100 mL). Trityl chloride (120 g, 0.45 mol) was added and the solution stirred for 36 hr. The resulting solution was extracted with 1N HCl and the organic layer evaporated to dryness. The residue was suspended in 2-propanol/1N NaOH (300 mL/100 mL) and refluxed for 3 hr. The solution was evaporated to a thick syrup and added to dichloromethane (500 mL). Water was added and acidified. The phases were separated, and the organic layer dried over sodium sulfate and evaporated to dryness. The residue was suspended in hot 2-propanol, cooled, and filtered to give 43.5 g (58%) of 6-(trityl-amino)caproic acid, useful as an intermediate compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].Cl>O1CCOCC1>[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of aniline (11 mmol), cyanamide (420 mg, 10 mmol), and HCl (3 mL of 4N in dioxane, 12 mmol) in 1,4-dioxane (10 mL) was heated in a sealed tube at 60° C. overnight. The reaction was concentrated in vacuo and the residue partitioned between NaOH (2N) and dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford N-phenyl-guanidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]([F:27])([F:26])[C:20]([NH:22][CH2:23][C:24]#[CH:25])=[O:21]>>[F:18][C:19]([F:27])([F:26])[C:20]([NH:22][CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1)=[O:21]
Reactant: CCCC(O)(C#Cc1cccc(Br)c1)CCC
Reactant: C#CCNC(=O)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(C#CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
4-((3-bromophenyl)ethynyl)heptan-4-ol was coupled with 2,2,2-trifluoro-N-(prop-2-ynyl)acetamide following the procedure described in Example 10 to give 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)prop-2-ynyl)acetamide as a pale yellow oil. Yield (0.083 g, 6%): 1H NMR (400 MHz, DMSO-d6) δ 10.03 (t, J=5.2 Hz, 1H), 7.40-7.33 (m, 4H), 5.16 (bs, 1H), 4.25 (d, J=5.6 Hz, 2H), 1.61-1.39 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.IC.[OH-].[Na+].F[C:18]1C=CC=CC=1C1C=CN(C)N=1>CO.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:18])[N:10]=[CH:11][CH:12]=1
Reactant: Fc1ccccc1-c1cc[nH]n1
Reactant: Cn1ccc(-c2ccccc2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1nccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 72 %

Procedure:
To a solution of 3-(2-fluorophenyl)-1H-pyrazole (8.62 g, 53.2 mmol, 1.0 eq.) in methanol (133 mL) under nitrogen at 0° C. were added iodomethane (4.3 mL, 68.9 mmol, 1.3 eq.), NaOH (aq., 6 N, 34 mL, 204.0 mmol, 3.8 eq.) and nBu4NBr (0.68 g, 2.11 mmol, 0.04 eq.). The cold bath was then removed, and the reaction mixture was stirred to room temperature. After 6.5 h, iodomethane was added (4 mL), and the reaction mixture was stirred overnight. More iodomethane (4 mL) and NaOH (aq., 6 N, 20 mL) were added, and the reaction mixture was stirred overnight. It was then concentrated in vacuo not to dryness, diluted with EtOAc, and the two layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (15:2) as eluent afforded a mixture of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole and 5-(2-fluorophenyl)-1-methyl-1H-pyrazole (6.78 g, 72% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH:23][C:24](=O)[CH2:25][Cl:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8].CC1NC=CN=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:24]([CH2:25][Cl:26])=[N:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16]1)=[O:8]
Reactant: CCOC(=O)C(N=Nc1ccccc1C(=O)c1ccccn1)NC(=O)CCl
Agent: Cc1ncc[nH]1
Solvent: CCO
Product: CCOC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1

Procedure:
A solution of 11.0 g. of ethyl [2-(2-pyridinecarbonyl)-phenyl]azo-(2-chloroacetamido)acetate and 2.5 g. of 2-methylimidazole in 500 ml. of ethanol is refluxed for one hour, followed by evaporation of the solvent. The residue is made alkaline with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate, followed by evaporation of the solvent to give ethyl 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate as crystals. Recrystallization from acetone-n-hexane gives colorless prisms, melting at 129° to 130° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][C:12]([CH3:24])([NH:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:13]#[N:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(O)C.[Na+].[Cl-]>C1COCC1>[NH2:14][CH2:13][C:12]([NH:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])([CH2:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:24]
Reactant: CC(NC(C)(C#N)CC1=Cc2ccccc2CC1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(NC(C)(CN)CC1=Cc2ccccc2CC1)c1ccccc1
Temperature: 20 °C

Procedure:
A solution of 16 g of the compound obtained in Step 1 in 200 ml of THF is added dropwise to a suspension, maintained under nitrogen, of 2.28 g (60 mmol) of LiAlH4 in 200 ml of THF. The temperature of the mixture is then increased to 20° C. and stirring is maintained at that temperature for 3 hours. The mixture is again cooled to 0° C. and hydrolysed by successive additions of 20 ml of iPrOH and 25 ml of saturated NaCl solution. The precipitate formed is suctioned off and rinsed with THF; the filtrate is concentrated in vacuo and the residue is chromatographed on silica, eluting with a mixture of CH2Cl2 /CH3OH/NH4OH=97/3/0.3, to yield the title compound in the form of 2 diastereoisomers:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Li+].Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[CH:16]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:15]3[CH:16]=[C:17]([O:23][CH3:24])[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chlorooxindole (0.94 g, 5.34 mmol) (Cresent Chem.) in N,N-dimethylformamide (20 mL) at room temperature was added lithium hydride (86 mg, 10.7 mmol) (Aldrich). The mixture was stirred at room temperature for 10 minutes, then 6-chloro-2,4-dimethoxy-pyrimidine (0.93 g, 5.34 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The mixture was cooled to room temperature. Water (100 mL) was added, and mixture was extracted with ethyl acetate (2×100 mL). The organic layers were separated, combined, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate) to give rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.23 g, 14%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56](Cl)=[O:57])=[CH:55][C:50]=2[O:49][CH2:48]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]([N:43]3[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]4[CH:30]=[CH:31][C:32]5[NH:33][C:34]6[N:35]=[C:19]([NH:20][C:21]7[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=7)[CH2:26][CH2:27][C:28]=4[CH:36]=5)[N:18]=[CH:17][C:16]=6[Cl:15])=[O:39])[CH2:41][CH2:42]3)=[O:57])=[CH:55][C:50]=2[O:49][CH2:48]1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)c2ccc3c(c2)OCO3)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1,3-benzodioxole-5-carbonyl chloride as starting materials in 16% yield. LCMS for C32H30ClN6O4 (M+H)+: m/z=597.2.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1cccc(Cl)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3-chloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=231 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cccc(Oc2ccccc2)n1
Temperature: 160 °C

Procedure:
2,6-Dibromo-pyridine (2 g, 8.44 mmol) and phenol (0.794 g, 8.44 mmol) were dissolved in DMSO (20 mL) and potassium tert-butoxide (0.947 g, 8.44 mmol) was added. The reaction was heated to 160° C. overnight then allowed to cool to room temperature. The reaction was submitted to aqueous workup and silica gel chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([Cl:24])[CH:26]=1)=[O:5])[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-chloro-aniline as starting materials. tR: 1.45 min (LC-MS 2); ESI-MS: 510.1/512.1 [M+H]+ (LC-MS 2).