Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[CH:29]6)=[CH:34][CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, white solid (72 mg, 58%), MS (ISP) m/z=500.4 [(M+H)+], mp 234° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:15]([CH:18]=[C:19]=[O:20])(=[O:17])[CH3:16]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH2:18][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of 3-chloro-4-morpholinoaniline (2.05 g, 9.64 mmol) in EtOAc (30 mL) was added acetyl ketene (1.62 g, 19.3 mmol) with stirring and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a pale yellow solid (2.59 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:19]Br.O>CN(C)C=O>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:3][C:2]=2[O:1][CH2:19]1
Reactant: O=C(CCc1ccc(O)c(O)c1)N1CCCC1
Reactant: BrCBr
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc2c(c1)OCO2)N1CCCC1
Reaction time: 4 h

Procedure:
0.92 g of N-[3-(3,4-dihydroxyphenyl)-propionylpyrrolidine was dissolved in 10 ml of N,N-dimethylformamide and then 1.2 g of dibromomethane and 1.2 g of potassium carbonate anhydride and 100 mg of cupric oxide were added to the solution and the resulting solution was stirred at 130°-140° C. for 4 hours. After cooling, the solution was poured over iced water, extracted with ethyl acetate, washed with water and then dried with sodium sulfate anhydride. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on a silica gel column with a mixed solvent (chloroform:methanol=100:l) and thus 0.59 g of oily N-[3-(1.3-benzodioxol-5-yl)propionyl]pyrrolidine was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (62.0 mg). Yield 31.3%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](/[CH:12]=[CH:13]/[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:5]=1)(=O)[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH:1]([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](/[CH:12]=[CH:13]/[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:5]=2)[CH3:2])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: COC(=O)NC/C=C/c1cc(C(C)=O)cc(OC)n1
Product: COC(=O)NC/C=C/c1cc(C(C)NC2CC2)cc(OC)n1

Procedure:
Methyl [(2E)-3-(4-acetyl-6-methoxypyridin-2-yl)prop-2-en-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate [Ex(298-2)] as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[O:5])C.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[OH:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)=[O:5])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1O
Solvent: Cc1ccccc1
Product: COc1cc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1OC
Temperature: 190 °C

Procedure:
A mixture of 6,7-dimethoxy-4-hydroxy-3-quinoline carboxylate ethyl ester (J. Am. Chem. Soc., 68, 1264 (1946)) (139 mg) and 4-chlorobenzylamine (0.61 mL) are heated at 190° C. for 1 h. The resulting mixture is diluted with toluene (1.5 mL) and allowed to cool to rt. The crude product is purified by column chromatography (dichloromethane/methanol; 100/1, 100/5) and recrystallization (acetic acid, water) to afford 26 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12](Cl)(=O)=O)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(O)C>O.Cl.[Zn]>[Cl:1][C:2]1[C:3]([SH:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(S)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
Zinc dust (14.4 g, 0.22 mol) was added to a solution of mercuric chloride (2.86 g, 10.6 mmol) in water (42 mL) and concentrated hydrochloric acid (1.7 mL). The mixture was stirred for 15 min and the supernatant poured off. The residue was washed with water (2×15 mL), ethanol (2×15 mL) and diethyl ether (2×15 mL). 5-chloro-6-chlorosulfonyl-3H-benzooxazol-2-one (12.3 g, 46 mmol) and ethanol (70 mL) were added to the residue and the mixture placed in an ice-bath. Concentrated hydrochloric acid (36 mL) was added via addition funnel over 15 min and the resulting mixture stirred at reflux for 18 hours. The cooled reaction mixture was poured into ice-cold water (300 mL) and stirred for 20 min. The precipitate was collected to give 9.5 g of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1)=[O:28]
Reactant: Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of 5.00 g 2-(2-amino-5-chlorophenyl)-2,3-dihydro-1H-indole in 70 ml CH2Cl2 at 10° C. were added 3.14 ml triethylamine and then dropwise 2.52 ml trimethylacetylchloride. The resulting solution was stirred for one hour at 10° C. and then quenched with water. The organic phase was separated, washed with 7.5% NaHCO3 and saturated NaCl, dried (MgSO4), and concentrated to yield 5.67 g solid. Recrystallization from cyclohexane yielded 3.09 g solid, m.p. 195°-198° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([N:23]1[CH2:24][CH2:25][N:20]([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:21][CH2:22]1)=[O:12])(=[O:3])=[O:4]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid (Example A3) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light brown crystalline solid (yield 57%). MS (m/e): 475.0 (M+H+, 100%), 492.3 (M+NH4+, 90%).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14](=[O:29])[CH2:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2.FC1C=C2C(C(=O)CC(C3C=CC(C)=CC=3)=N2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([O:29][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])=[CH:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2
Reactant: Cc1ccc(C2=Nc3cccc(F)c3C(=O)C2)cc1
Reactant: O=C(CBr)N1CCOCC1
Agent: Cc1ccc(C2=Nc3cc(F)ccc3C(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(F)cccc3n2)cc1
Temperature: 20 °C
Yield: 18 %

Procedure:
4-(2-Bromoacetyl)morpholine (7.3 g) in 2 butanone (50 cc) is added to a stirred suspension of a mixture (11.2 g of 5-fluoro-2-(4-methylphenyl)-4-quinolone and 7-fluoro-2-(4-methylphenyl)-4-quinolone and anhydrous potassium carbonate (11.3 g) in 2-butanone (250 cc). The mixture is heated to reflux for 15 hours and cooled to room temperature (approximately 20° C.), the insoluble matter is removed by filtration and the 2-butanone is evaporated off under reduced pressure. The residue is taken up with water (200 cc) and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is separated after settling has taken place, dried and evaporated under reduced pressure. After chromatography of the residue on silica gel by means of cyclohexane/ethyl acetate mixture (70:30 by volume) as eluant, the solid obtained is ground in 40°-60° C. petroleum ether (100 cc). 4-≡[5-fluoro-2-(4-methylphenyl-4-quinolyl]oxyacetyl}morpholine (2.4 g), m.p. 142°-4° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 40 g, 165 mmol) in anhydrous DMF (320 mL) was added at ambient temperature potassium carbonate (45.7 g, 331 mmol). 2-(Chloromethyl)-6-methylpyridine hydrochloride (31 g, 174 mmol) was added in portions, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water (800 mL) and methylene chloride (1000 mL). The phases were separated and the aqueous phase was extracted further with methylene chloride (200 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown solid. The crude product was triturated with ether (400 mL) and the solids were collected by filtration, washed with ether, and dried under vacuum to afford the desired product as brown solid (46 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[NH:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[N:8]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN[C@H](C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)[C@H](C)C(=O)OC(C)(C)C

Procedure:
N-Allyl-D-alanine t-butyl ester (69) is treated with 1.1 equivalents of benzyl chloroformate and 1.1 equivalents of triethylamine in methylene chloride at room temperature overnight. After evaporation of solvent, the product is purified by silica gel chromatography to give (70).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])(C)C)[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (28 mg, 0.10 mmol) and 4-bromo-benzenesulfonamide (24 mg, 0.10 mmol) according to general procedure II. Obtained as a yellow solid (12 mg, 27%). MS (ISP) 439.0 [(M+H)+]; mp 238-240° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)[CH:20]=1)[CH2:16][CH3:17])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]3[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:17]
Reactant: NCCc1cccc(O)c1
Reactant: CCN(CCC1CCCN1C(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(CC[C@@H]1CCCN1)Cc1cccc(-c2ccnc(NCCc3cccc(O)c3)n2)c1

Procedure:
Intermediate 107 was coupled with 3-(2-Amino-ethyl)-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.62 (s, 1H), 8.36 (d, 2H), 7.94 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H), 7.05 (t, 1H), 6.78 (s, 2H), 6.59 (d, 1H), 4.53 (m, 2H), 3.90 (m, 2H), 3.58 (m, 2H), 3.32 (m, 5H), 3.00 (t, 2H), 2.22 (m, 3H), 2.02 (m, 2H), 1.71 (m, 1H), 1.40 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[N:29][CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH:1]1([C:4]2[C:12]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:2][CH2:3]1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Reactant: OCc1cncc(Br)c1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cncc(CO)c1)c2C1CC1
Temperature: 130 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, (50 mg, 0.160 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 36 mg, 0.192 mmol), 1,2-dimethoxyethane (1.0 mL), and 2 M aqueous sodium carbonate (0.200 mL, 0.40 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (73 mg, 0.008 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 1 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 4-Cyclopropyl-5-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 295.14485 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.17-0.25 (m, 2H), 0.72-0.80 (m, 2H), 1.87-1.98 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 4.83 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.80 (t, J=2.0 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:14]([NH:15][N:16]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1)[CH3:10])=[O:17])[CH3:20]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1cccc(C(F)(F)F)c1
Yield: 99 %

Procedure:
m-Trifluoromethylacetophenone (74 g, 0.394 mole), ethyl carbazate (43 g, 0.413 mole), and catalytic p-toluenesulfonic acid (20 mg) were refluxed under N2 over a Dean-Stark trap in toluene (1.2 L) until the theoretical amount of water of reaction was removed (7.1 mL, 6 h). The solvent was then removed in vacuo and 2-(1-(3-(trifluoromethyl)phenyl)ethylidene)hydrazinecarboxylic acid ethyl ester (107 g, 100% yield) was obtained as a white solid which was recrystallized from cyclohexane, mp=94°-96° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1cc(Cl)ccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-Bromo-5-chloroaniline (CAS#823-57-4; 5 g), 4-fluorophenylboronic acid (3.56 g) and cesium carbonate (31.6 g) were combined in THF (70 ml) and water (35 ml). The mixture was degassed by bubbling argon through the solution. After addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886 mg) the reaction mixture was stirred 1 h at 80° C. in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SO4, evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally bulb-to-bulb distilled at 0.3 mbar and 120-130° C. oven temperature to give the title compound (5.07 g) as a light yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:16][CH2:15]1
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH2Cl2 (100 mL) at 0° C., ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, 11.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min., after which time the mixture was partitioned between CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (50 mL×2) and the combined organic phase dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by solid phase extraction on a 500 mg aminopropyl column (International Sorbent Technologies) eluting with chloroform (30 mL×2) and ethyl acetate (50 mL) to give 800 mg of the title compound (69%).
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Br:9])[C:2]=2[Br:1])=[O:19])=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(Br)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(Br)c2Br)cc1

Procedure:
The amide was prepared according to Example 18 from 2,3-dibromoaniline, 4-tert-butylbenzoyl chloride and diisopropylethylamine in dioxane. MS (ESI) m/z 408; HPLC Method B, purity 80.6% at 210-370 nm, 11.4 min.; 74.9% at 240 nm, 11.4 min.; HRMS: calcd for C17H17Br2NO+H+, 409.97496; found (ESI, [M+H]+), 409.9775.