Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1.O.[Cl-].[Zn+2].[Cl-]>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:1][C:2]2[C:15]3[C:10]([N:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: Cc1c2ccccc2nc2ccccc12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Temperature: 130 °C
Yield: 35 %

Procedure:
A mixture of 9-methylacridine (4.83 g, 25.0 mmol), 4-nitrobenzaldehyde (4.23 g, 31.25 mmol) and zinc chloride (5.06 g, 31.25 mmol) is heated at 130° C. for 3 hours with an oil bath. The solid recovered is heated in a solution of sodium metabisulfite in order to eliminate the excess aldehyde and the hot mixture is filtered. Precipitates obtained are dissolved in a minimum amount of tetrahydrofuran and water is added to the solution so as to obtain the product in the form of precipitates. These precipitates are recovered by filtration and dried. The product can be recrystallized from ethanol. The yield is 35%.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:30]Br.O>C(O)(=O)C>[Br:30][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cc2c(Br)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a rt solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole (1.16 g, 0.0024) in acetic acid (20 mL, glacial) was added Br2 (1.2 g, 0.008 mol in acetic acid) dropwise. The mixture was stirred for an additional 10 min and water (10 mL) was added. The mixture was extracted with EtOAc (100 mL). The organic layer was separated and dried (MgSO4) and concentrated. Purification via ISCO normal phase chromatography (SiO2, 5-15% ethyl acetate/hexanes) to provide 4-bromo-5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole as the regioselective bromination product: MS (ES) m/z 485 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[OH-].[Na+].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1>COCCOC.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:15]1[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: Clc1cccc(Cl)c1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichlorobromobenzene (3.5 g, 15.7 mmol) and sodium hydroxide (3.14 g, 78.5 mmol) in DME-water (2:1) was added 5-fluoro-2-methoxybenzene boronic acid (4.0 g, 23.5 mmol) at 90° C., followed by tetrakis(triphenylphosphine)palladium (0) (0.9 g, 0.78 mmol). The reaction mixture was heated at 90° C. overnight and cooled to room temperature. The mixture was extracted with methylene chloride and washed with water. The organic solvent was removed under vacuum. Chromatography with 5% ethyl acetate in hexanes afforded 2.62 g (87%) of 2′,6′-dichloro-5-fluoro-2-methoxybiphenyl as a colorless oil. MS (EI) m/z 270 (M+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH3:4].I[CH3:16]>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1([CH2:13][O:14][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1(CO)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.9 %

Procedure:
60% Sodium hydride in mineral oil (6.2 g, 130.8 mmol) is added to a solution of 1-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (15.0 g, 87.2 mmol) in 100.0 mL of THF at 0° C., followed by the addition of iodomethane (13.6 g, 95.9 mmol) and the reaction mixture is stirred at room temperature for 14 hours. After this time, the reaction mixture is quenched with ice water and then extracted with ethyl acetate twice. The organics are combined and washed with water twice then brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 12.0 g of the title compound. Yield: 74%; m/z 209 [M+Na].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CCCCCCCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of I (4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.44 ml of diiodooctane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C32H36F2INO3 (647) MS (ESI): M+-18
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18]([O:23]C)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:15]1
Reactant: COc1nccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=c1[nH]ccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Yield: 63.5 %

Procedure:
After dissolving 296 mg of (E)-3-[4-[2-(2-fluorophenyl)vinyl]piperidino]methyl-2-methoxypyrazine in 5 ml of ethanol, 1 ml of thionyl chloride was added and the mixture was heated to reflux for 9 hours. Aqueous sodium carbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the mixture was filtered to obtain the title compound (180 mg, 63% yield).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[CH2:5]1.[N+](C1C=CC([O:32][C:33]([N:35]2[CH:39]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=3)[CH:38]([CH:48]3[CH2:50][CH2:49]3)[O:37][C:36]2=[O:51])=O)=CC=1)([O-])=O>>[ClH:1].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:12]2([OH:15])[CH2:11][CH2:10][CH:9]([N:6]3[CH2:7][CH2:8][C@@H:4]([NH:3][C:33]([N:35]4[C@@H:39]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=5)[C@H:38]([CH:48]5[CH2:50][CH2:49]5)[O:37][C:36]4=[O:51])=[O:32])[CH2:5]3)[CH2:14][CH2:13]2)=[CH:21][CH:20]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Reactant: N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Agent: Cl
Product: O=C(N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1)N1C(=O)O[C@@H](C2CC2)[C@@H]1c1ccc(F)c(F)c1

Procedure:
This compound was prepared from the product of Example 35, Step D and the product of Example 43, Step C by a procedure similar to that described in Example 25, Step E. ##STR87##
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:12]([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH:11]=2)C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]C(NC2C=CC(SC(C)C)=C(C=2)CN(C)C(=O)OC(C)(C)C)=O)=[C:36]([CH2:66][CH3:67])[CH:35]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])=[C:12]([CH:11]=2)[CH2:22][N:23]([CH3:24])[C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:7])=[C:36]([CH2:66][CH3:67])[CH:35]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CCc1cc(Br)ccc1CCCC(=O)Nc1ccc(SC(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCc1cc(Br)ccc1CCCC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Yield: 69 %

Procedure:
Using a procedure analogous to that described for the preparation of 16G, 21B (0.700 g, 1.25 mmol) was reacted with mCPBA (0.695 g, 3.10 mmol) to give 21C (0.513 g, 69%). MS (ESI) m/z 595, 597.4 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:19]=3[O:26]C)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[OH:26])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn(C3CCC3)c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCC3)c3c(C(F)(F)F)cccc23)c(O)c1
Yield: 41 %

Procedure:
Prepared according to Method D step C from 1-cyclobutyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.575 g, 1.5 mmol), boron tribromide (0.866 mL, 9.1 mmol) and 0.5 mL of cyclohexene to give the product (0.214 g) as an off-white solid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[C:21](=O)[CH2:20][O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].B#B>O1CCCC1>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:30])([F:31])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OCC2=O)cc1
Agent: B#B
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared by analogy to Example 74b by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one (diastereomer B) with diborane in tetrahydrofuran, followed by purification of the base on a silica gel column using toluene/ethyl acetate=8:2 as eluant.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:38]=[N+:39]=[N-:40])(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:38]1[C:1]([C:3]2[CH:4]=[C:5]([N:9]3[C:18]4[CH:17]=[CH:16][C:15]5[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=5[C:13]=4[NH:12][C:11](=[O:23])[C:10]3=[O:24])[CH:6]=[CH:7][CH:8]=2)=[N:2][N:40]=[N:39]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2cccc(-c3nnn[nH]3)c2)c1=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To an anhydrous toluene (1 mL)-anhydrous DMF (1.5 mL) solution of 4-(3-cyanophenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione (20 mg, 0.064 mmol) was added tri-n-butyltin azide (53 μL, 0.192 mmol), and the mixture was stirred at 110° C. for 18 hours. After cooling on standing, the reaction mixture was poured into a 1M aqueous sodium hydroxide solution, and washed with ethyl acetate. After neutralization of the aqueous layer by addition of a 1M aqueous hydrochloric acid solution, the precipitated solid was collected by filtration, washed with water, and dried to obtain the titled compound as a white crystal (15 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:38])[CH2:36][CH3:37]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:38][CH2:35][CH2:36][CH3:37])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 100 mg (0.19 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 30 μl (0.37 mmol) of n-propylamine were stirred in 2.5 ml of THF for 2 h. The reaction mixture was then purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 67 mg (64% of theory) of the target compound.
Reaction SMILES: CN(CCN(C)C)C.[O:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Li]CCCC.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].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>[CH3:30][C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:22]=1)([CH3:29])[C:27]#[N:28]
Reactant: c1ccoc1
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C#N)c1ccc(-c2ccco2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a cooled (0° C.) mixture of TMEDA (11.4 mL, 76 mmol) and THF (75 mL) was added furan (5.7 mL, 78 mmol) followed by n-BuLi (15 mL, 2.5M in hexanes). The resulting solution was stirred for 30 min then ZnCl2 added (60 mL, 0.5M in THF). To this solution was added a solution comprised of (4-bromo-phenyl)-2,2-dimethyl-acetonitrile (4.48 g, 20 mmol) (reference example 30a) and (Ph3P)4Pd (460 mg, 0.4 mmol) in THF (10 mL). The resulting mixture was warmed to 50° C. and stirred at this temperature for 2.5 hr. The reaction mixture was allowed to cool to room temperature, diluted with ether, then washed, sequentially, with aqueous hydrochloric acid (2M) and brine, then dried over MgSO4 and concentrated. The residue was purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give 3.9 g of the title compound as an oil. 1H NMR (CDCl3) d 1.74 (s, 6H), 6.47 (dd, J=2, 1 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 7.47 (m, 3H), 7.68 (m, 2H), MS (EI) m/z 211 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:7]([O:23][CH3:22])=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Reaction time: 1 h

Procedure:
To a solution of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (Intermediate 12. 700 mg, 1.7 mmol) in THF (20 mL) was added NaOMe solution at −78° C. (which was prepared by dissolving Na metal (39 mg, 1.7 mmol) in 4 mL of methanol). The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to yield 2,5-difluoro-N-(2-fluoro-4-iodophenyl)-3-methoxy-6-nitrobenzenamine as yellow solid (597 mg). 1H-NMR (400 MHz, CDCl3): δ 3.95 (3H, s), 6.51-6.56 (1H, m), 6.57-6.65 (1H, m), 7.34 (1H, d, J=8.8), 7.42 (1H, dd, J=1.6, 10), 7.7 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[N:21]=[C:20]([O:25][CH3:26])[N:19]=1>C(N(CC)CC)C>[Cl:17][C:18]1[N:19]=[C:20]([O:25][CH3:26])[N:21]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]3)=[C:4]([O:15][CH3:16])[CH:3]=2)[N:23]=1
Reactant: COc1cc(N)ccc1-n1cnc(CO)c1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Product: COc1nc(Cl)nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)n1
Yield: 61 %

Procedure:
This compound was prepared in analogy to example 8 from [1-(4-amino-2-methoxy-phenyl)-1H-imidazol-4-yl]-methanol, triethylamine and 2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound was isolated as a brownish solid in 61% yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[I:33]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[I:33])[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1I
Reactant: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Fc1cc2c(cnn2Cc2ccccc2I)cc1SCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-(benzylthio)-6-fluoro-1H-indazole (1-2, 1.5 g, 5.81 mmol, 1.0 equiv) in NMP (29.0 mL) was added cesium carbonate (5.68 g, 17.42 mmol, 3.0 equiv) and 1-(bromomethyl)-2-iodobenzene (2.59 g, 8.71 mmol, 1.5 equiv) and the reaction mixture was stirred at ambient temperature. Upon completion, the reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography followed by reverse phase chromatography (50%→100% 0.1% TFA in ACN: 0.1% TFA in water) to yield the desired regioisomer. ESI+ MS [M+H]+ C21H16FIN2S: 475.1 found, 475.3 required.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[CH2:20]([NH:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:20]([N:22]([C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1)[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21]
Reactant: Cc1noc(-c2cn3ncnc(Cl)c3c2C(C)C)n1
Reactant: CCNc1cnc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1cnc2[nH]ccc2c1)c1ncnn2cc(-c3nc(C)no3)c(C(C)C)c12

Procedure:
The procedure described above in Example 24 was employed. Thus, when 4-chloro-5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine (86 mg, 0.31 mmol), ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine (50 mg, 0.31 mmol) and diisopropylethylamine (162 μL, 0.93 mmol) in DMF (2.0 mL) were used, the title compound was obtained. LCMS; m/z 403 (M+H)+. Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 9.70 (1H, s), 8.20 (1H, s.), 8.02 (1H, s), 7.52 (1H, s), 7.29 (1H, s), 6.38 (1H, br. s.), 4.10 (2H, q, J=6.8 Hz), 3.24(1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz). (1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2cccc(C(F)(F)F)c2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(Cc5cccc(C(F)(F)F)c5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[5-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazol-2-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:19])[CH3:18].O>C1COCC1>[C:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27])=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ex-33A: To a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.74 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) in 25 ml THF, 4-acetylbenzenesulfonyl chloride(1.1 g, 5 mmol) was added at 0° C. The mixture was stirred overnight and then poured into H2O. The precipitate was filtered, dried, and recrystallized from EtOAc/Hexene to give 1.3 g (76.8%) of 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.11 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 6.59 (b, 1H), 2.67 (s, 3H), 0.89 (s, 9H), 0.20 (s, 6H).