Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N=C=N.[CH3:4][O:5][CH2:6][C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]([N:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])=[C:30]([Br:45])[C:29]2=[O:46])[CH:25]=[CH:26][CH:27]=1.CN=C=O>CN(C)C(=O)C.CN1CCOCC1.ClCCCl>[Br:45][C:30]1[C:29](=[O:46])[N:28]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[CH2:21][NH:20][C:7](=[O:9])[CH2:6][O:5][CH3:4])[C:33]([CH3:34])=[CH:32][C:31]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44]
Reactant: COCC(=O)O
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Agent: CN=C=O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: COCC(=O)NCc1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added approximately 2.87 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by a stock solution of methoxyacetic acid (8.0 mL, 0.10 M) in N,N-dimethylacetamide. A stock solution of 1-hydroxybenzotriazole in N,N-dimethylacetamide (3.0 mL, 0.10 M) and N-methylmorpholine (6.0 mL, 0.10 M) in 1,2-dichloroethane were added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. A stock solution of EXAMPLE 293 in N,N-dimethylacetamide (5.0 mL, 0.10 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with 1,2-dichloroethane (10 mL) and treated with approximately 1.70 g of polyamine resin (2.63 mmol/g) and approximately 0.84 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with N,N-dimethylacetamide (2×5 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded an off white solid (0.081 g, 28%). 1H NMR (400 MHz, DMF-d6) δ 7.59 (q, J=7.65 Hz, 1H), 7.46 (app t, J=7.55 Hz, 1H), 7.40-7.37 (m, 1H), 7.11-7.07 (m, 2H), 7.00 (t, J=8.56 Hz, 2H), 6.54 (s, 1H), 5.30 (s, 2H), 4.43 (s, 2H), 3.88 (s, 2H), 3.35 (app d, J=0.80 Hz, 2H), 1.97 (s, 3H). ES-HRMS m/z 507.0699 (M+H C23H21BrF2N2O4 requires 507.0726).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Reaction of 100 g of 5-chloro-2-nitrobenzoic acid and 103.3 g of phosphorus pentachloride in 400 ml of cyclohexane at reflux for 80 minutes followed by treatment of the crude product 3 times with carbon tetrachloride gave 5-chloro-2-nitrobenzoyl chloride. A solution of the acid chloride in 50 ml of tetrahydrofuran was added to a warm solution of 91.3 g of 5-aminotetrazole monohydrate in 500 ml of tetrahydrofuran and 20 ml of water. A precipitate formed, and the mixture was allowed to stand for 4 hours. It was then diluted with water and the solid was separated by filtration and air dried to give 5-chloro-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 268°-269° C., after recrystallization from dimethylformamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].CN(C)CCN(C)C.ICCCCI>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: ICCCCI
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N′,N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dilute HCl (pH 1) and water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[C:6](=[O:15])[NH:7][C:8]([CH2:12][CH2:13][CH3:14])=[N:9][C:10]=1[CH3:11].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]=[C:38](C(Cl)(Cl)Cl)[O:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-:45].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[C:6](=[O:15])[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:45])[O:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]([CH2:12][CH2:13][CH3:14])=[N:9][C:10]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCCc1nc(C)c(Cc2cccc(F)c2F)c(=O)[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Cc2cccc(F)c2F)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 15.4 %

Procedure:
To a solution of 5-(2,3-difluorobenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one (0.55 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.03 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate (0.44 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in acetone (10 mL), 1 M sodium hydroxide (2 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.11 g, 20%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[CH2:25]=[C:26]([CH3:28])[CH3:27].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH:12]1([NH:11][S:8]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([Br:16])[CH:18]=2)[CH2:25][C:26]3([CH3:28])[CH3:27])(=[O:10])=[O:9])[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(S(=O)(=O)NC2CCC2)cc1
Reactant: O=Cc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 4-amino-N-cyclobutyl-benzenesulfonamide (2.8 g, 12.4 mmol) and 3-bromo-benzaldehyde (2.52 g, 13.6 mmol) in acetonitrile (150 mL) were added isobutene (2.7 mL, 37.2 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.54 g, 2.5 mmol). The resulting mixture was stirred at 80° C. for 18 h in sealed tube, then diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (2.2 g, 40%) as a light yellow solid: MS (ESI) M+1=449.0 & 451.0.
Reaction SMILES: Br.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=3)[N:10]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A mixture of 0.5 g 4-(4-methyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.39 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 50 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.46 g of 4-methyl-N-[4-(4-methyl-phenyl)-thiazol-2-yl]-benzenesulfonamide was obtained as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]2[NH:10][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:12][C:7]2=[N:6][CH:5]=1.[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[Br:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:12]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:7]2=[N:6][CH:5]=1.[Br:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:12][C:7]2=[N:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ncc(Br)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2nc(Br)cnc2n1COCC[Si](C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ncc(Br)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 60% dispersion of NaH (75 mg, 1.9 mmol) was added to a stirred solution of (S)-tert-butyl 2-(6-bromo-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (627 mg, 1.70 mmol) in DMF (15 mL) and the reaction was stirred for 1.5 h at room temperature. Then SEM-Cl (0.30 mL, 1.7 mmol) was added and the reaction was stirred overnight. The reaction was diluted with water (˜30 mL) and EtOAc (˜35 mL), the layers were separated and the organic layer was washed with brine (30 mL), dried (MgSO4), filtered and concentrated. The crude yellow oil was purified by flash chromatography (40 g SiO2, 20-30% EtOAc/hexanes) to yield (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (421 mg) as a clear colorless oil and (S)-tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (345 mg) as a clear colorless oil. The absolute regiochemistry of the SEM group was not established unambiguously, the names (and structures) may be exchanged in these intermediates.
Reaction SMILES: C(O[C:4]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH3:13])[CH2:6][CH:5]=1)C.N[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.C1(N)C(F)=C(F)C(F)=C([NH2:33])C=1F.Cl.Cl>>[CH3:15][C:16]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:33]=[C:4]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH3:13])[CH2:6][C:5]=12
Reactant: NCC(=O)c1ccccc1
Reactant: CCCN1CC=C(OCC)CCC1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CCCN1CCCc2nc3ccccc3c(C)c2C1

Procedure:
2,3,4,5-tetrahydro-11-methyl-2-propyl-1H-azepino[4,3-b]quinoline and their dihydrochlorides were prepared from 4-ethoxy-1,2,6,7-tetrahydro-1-propyl-5H-azepine and 2amino-acetophenone analogous to Example 217. Yield of the dihydrochloride of the [4,5-b]-isomer: 15% of theory; m.p. 245-246° C. Yield of the dihydrochloride of the [4,3-b]-isomer: 10% of theory; m.p. 282° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>COCCOC.C(O)C.O1CCCC1>[CH3:1][N:2]([CH3:18])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:8][CH2:7][CH:6]([C:29]#[N:30])[CH2:5][CH2:4]1
Reactant: COc1cccc(C2(N(C)C)CCC(=O)CC2)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1cccc(C2(N(C)C)CCC(C#N)CC2)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexanone (2.47 g, 10 mmol) and tosylmethyl isocyanide (2.54 g, 13 mmol) in anhydrous 1,2-dimethoxyethane (40 ml) and anhydrous ethanol (2 ml) was cooled to −30° C. A solution of potassium tert-butylate (2.70 g, 24 mmol) in anhydrous tetrahydrofuran (20 ml) was then added dropwise such that the internal temperature did not rise above 5° C. The mixture was stirred at 0° C. for 1 h, at room temperature for 24 h and then under reflux for 5 h. The reaction mixture was cooled to room temperature and filtered. The residue on the filter was washed with 1,2-dimethoxyethane. The filtrate was concentrated i. vac., the residue was taken up in diethyl ether and the solution was washed with water (3×20 ml) and saturated sodium chloride solution (20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (1.76 g) was purified by flash chromatography with ethyl acetate and then ethyl acetate/methanol (9:1→8:2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.8 %

Procedure:
{2-[4-(4-Chloro-phenoxy)-phenyl]ethyl}-carbamic acid tert-butyl ester (600 mg, 1.72 mmol, 1 eq) and TFA (658 μl) were dissolved in 50 ml of dry DCM under argon atmosphere. The mixture was stirred at room temperature for 60 hours. The solvent was evaporated, the resulting crude was dissolved in 10 ml of MeOH and was purified using 20 g SCX column. The free base was rinsed from the column using 1N NH3/ethanol solution. The solvent was evaporated and obtained was 2-[4-(4-chloro-phenoxy)-phenyl]-ethylamine (404 mg, yield=90.8%, purity=96%) in form of yellowish oil. MS: [M+H]+=248.21 1H NMR (300 MHz; CDCl3) 8/ppm 1.22 (s, 2H), 2.71 (t, J=6.62 Hz, 2H), 2.95 (t, J=6.62 Hz, 2H), 6.85-6.96 (m, 4H), 7.16 (d, J=7.60 Hz, 2H), 7.25 (d, J=7.60 Hz, 2H)
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=1)=O.[F:13][C:14]([F:27])([F:26])[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH2:24])[CH:22]=[C:17]2[CH:16]=1>C(O)(C)C.C(#N)C.CS(C)=O>[F:27][C:14]([F:13])([F:26])[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH:24][C:4]3[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=3)[CH:22]=[C:17]2[CH:16]=1
Reactant: CS(=O)c1cc(CC#N)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CC(C)O
Solvent: CC#N
Solvent: CS(C)=O
Product: N#CCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 80 °C
Yield: 8.4 %

Procedure:
A mixture of [6-(methylsulfinyl)-4-pyrimidinyl]acetonitrile (Intermediate 16, 150 mg, 0.828 mmol) and 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 178 mg, 0.828 mmol) in isopropanol (7 mL) was stirred and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and condensed. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (2.7 mL) and purified by MDAP (3 injections). Fractions containing the suspected product were combined and concentrated under reduced pressure. The solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (1.8 mL) and purified again by MDAP (2 injections). Fractions containing the suspected product were combined and concentrated under reduced pressure to give the title compound as a solid (23 mg);
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:7]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.O>C1COCC1>[Cl:20][C:5]1[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:7][C:2]2[NH:1][C:27](=[O:28])[O:21][C:3]=2[CH:4]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(O)cc2Cl)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Reaction time: 1 h
Yield: 62.6 %

Procedure:
0.6 g (1.9 mmol) of 3-(5-amino-2-chloro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.35 g (2.2 mmol) of CDI were dissolved in 5 ml of THF, followed by stirring for 1 hour under heating and refluxing. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.41 g (yield: 63%) of the desired product. Melting point: 263-265° C.
Reaction SMILES: [OH:1][CH:2]([CH:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)COS(C1C=CC(C)=CC=1)(=O)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[C:38](=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:22]1([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]([OH:1])[CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: CN1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)C(c2ccccc2)n2ccc3ccccc32)cc1
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1

Procedure:
A mixture of (2RS,3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (0.185 g, 0.4 mmol), 1-methyl piperazine (0.05 mL, 0.4 mmol) and potassium carbonate (0.07 g, 0.44 mmol) in acetonitrile (10 mL) was stirred at reflux under nitrogen for 24 hours. After cooling, the mixture was filtered and the filtrate was concentrated and purified via Biotage chromatography (5% methanol/dichloromethane) to give a white solid of (1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol. The free base was dissolved in a minimum amount of ethanol and treated with a 1 N ethereal solution of hydrochloric acid until the solution was pH=3 followed by diethyl ether. The product was then crystallized by adding a minimum amount of hexane to afford the titled compound, (1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol dihydrochloride as an off-white solid. MS m/z 350 ([M+H]+); HRMS: calcd for C22H27N30+H+, 350.22269; found (ESI, [M+H]+), 350.2228.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1C=CC(/C=C/[C:36]([NH:38][C:39]2C=CC(Cl)=C([N+]([O-])=O)C=2)=[O:37])=CC=1)(C)(C)C.CCO.[In]>[NH4+].[Cl-]>[C:19]([C:16]1[CH:15]=[CH:14][C:13](/[CH:12]=[CH:11]/[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:36]([NH:38][CH3:39])=[O:37])[CH:3]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cc1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc(Cl)c(N)c2)cc1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: CNC(=O)Nc1cc(NC(=O)/C=C/c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
(2E)-N-(3-Amino-4-chlorophenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a round-bottomed flask equipped with a magnetic stir bar, was added (2E)-3-[4-(tert-butyl)phenyl]-N-(4-chloro-3-nitrophenyl)prop-2-enamide, Example 156, (250 mg, 0.69 mmol), EtOH (8 mL), indium (800 mg, 6.9 mmol, Aldrich) and satd NH4Cl (10 mL). The reaction mixture was stirred at reflux for 5 h. The solvents were removed in vacuo, the residue was dissolved in EtOAc (20 mL), washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield the title product. MS (ESI, pos. ion) m/z: 329 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1.[CH3:14][O-:15].[Na+]>O1CCOCC1>[CH:11]1([NH:10][CH2:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:15][CH3:14])[C:7]=2[CH3:8])[CH2:13][CH2:12]1
Reactant: Cc1c(CNC2CC2)ccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nccc(CNC2CC2)c1C
Yield: 90.1 %

Procedure:
A mixture of (2-chloro-3-methylpyridin-4-ylmethyl)cyclopropylamine (10.0 g, 50.8 mmol) and sodium methoxide (13.73 g, 254 mmol) in dioxan (40 mL) was heated to reflux for 48 h. The reaction mixture was filtered through Celite, and the remaining solid was washed with Et2O (2×). The solvents were removed under reduced pressure. Purification by FC yielded the title compound (8.8 g, 90%) as a pale, yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:7]
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(C(=O)O)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccccc2O)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromo-4-methylbenzoic acid (1.0 g, 4.7 mmol) and thionyl chloride (18 mL) was refluxed for 1 h and then cooled to rt. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (10 mL), and was added to a cooled (0° C.) mixture of 2-aminophenol (510 mg, 4.7 mmol) and diisopropylethylamine (0.90 mL, 5.1 mmol) in THF (18 mL). The resulting mixture was stirred at rt for 4 h. The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5 to 1:4) to afford 3-bromo-N-(2-hydroxyphenyl)-4-methylbenzamide.