Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O1CCOCC1>[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)[O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: COC(=O)C(O)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)C(Oc1c(Cl)nc(Cl)nc1Cl)C1CC1
Reaction time: 6 h
Yield: 57.5 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidin-5-ol (250 mg, 1.25 mmol), cyclopropyl-hydroxy-acetic acid methyl ester (245 mg, 1.88 mmol) and triphenylphosphine (493 mg, 1.88 mmol) in THF (12 mL) was added DIAD (370 μL, 1.88 mmol) dropwise. The resultant suspension was stirred for 18 hours before the addition of dioxane (10 mL) and the reaction stirred for a further 6 hours. The heterogeneous mixture was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, gradient 0-30% ethyl acetate in cyclohexane) affording Cyclopropyl-(2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid methyl ester as a white solid (224 mg, 32%). LCMS: RT=3.66 min, [M+H]+=311/313/315.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.Br.[NH2:24][C:25]1[C:30]([CH2:31]Br)=[CH:29][C:28]([Br:33])=[CH:27][N:26]=1>CN(C=O)C>[C:9](=[N:8][CH:7]1[CH2:31][C:30]2[C:25](=[N:26][CH:27]=[C:28]([Br:33])[CH:29]=2)[NH:24][C:6]1=[O:22])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncc(Br)cc2CC1N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
NaH (60% dispersion in mineral oil, 1.2 g, 30 mmole) was added portionwise over 10 min to a solution of N-(diphenylmethylene)glycine ethyl ester (8.0 g, 30 mmole) in DMF (150 mL) with stirring under Ar at 0° C. The reaction was stirred for 15 min, then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (5.0 g, 14.4 mmole) was added in one portion. The reaction was allowed to warm to RT and stir for 18 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc (150 mL), hexane (150 mL), and H2O (150 mL). The resulting suspension was triturated and filtered, and the solid was dried under vacuum to give the title compound (3.27 g, 56%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.92 (s, 1H), 8.23 (s, 1H), 7.86 (s, 1H), 7.26-7.55 (m, 10H), 4.05 (dd, 1H), 3.10 (t, 2H); MS (ES) m/e 406.0 (M+H)+.
Reaction SMILES: C([O:4][C:5](=[O:35])[CH:6]([N:16]([C:26](=[O:34])[CH:27]([CH2:31][CH2:32][Cl:33])[C:28](=[O:30])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1>C1COCC1.CCOCC.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>[CH2:9]([O:8][CH2:7][CH:6]([N:16]([C:26](=[O:34])[CH:27]([CH2:31][CH2:32][Cl:33])[C:28](=[O:30])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:5]([OH:35])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCOC(=O)C(COCc1ccccc1)N(Cc1ccc(OC)cc1)C(=O)C(CCCl)C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCOCC
Product: COc1ccc(CN(C(=O)C(CCCl)C(C)=O)C(COCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.3 %

Procedure:
To a solution of allyl ester 76 (1.24 g, 2.47 mmol) in THF (20 mL) was added morpholine (646 mg, 7.41 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 7 h and diluted with Et2O (200 mL). The organic layer was washed with 0.2 N HCl and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on SiO2 (15:85 acetone:CH3Cl) to give acid 77 (620 mg, 75%). Data provided for only one diastereomer: IR (neat) 1721, 1639 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.20-7.40 (m, 7H), 6.89 (d, J=8.7 Hz, 2H), 4.82 (d, J=16.5 Hz, 1H), 4.70 (d, J=16.5 Hz, 1H), 4.48 (s, 2H), 4.41-4.45 (m, 1H), 4.00-4.10 (m, 3H), 3.84 (s, 3H), 3.50-3.65 (m, 2H), 2.20-2.50 (m, 2H), 2.13 (s, 3H); LRMS (ESI) Calcd. for C24H28ClNO6 [M−H] 460, found 460.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:21][C@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][C@@H:22]2[CH3:21])[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: -5 °C

Procedure:
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at −5° C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCC)(=O)CC(C)=O>>[OH:4][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CCOC(=O)CC(C)=O
Product: CC(O)CC(=O)OCc1ccccc1
Yield: 48 %

Procedure:
Benzyl 3-hydroxybutyrate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that benzyl acetoacetate was used to replace for ethyl acetoacetate. Yield 48%.
Reaction SMILES: F[C:2]1([O:9][C:10]#[C:11][CH3:12])[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][CH2:3]1.[Br:13]C1C=CC(F)=CC=1O.BrC1C=C(F)C=CC=1OCC#C>>[Br:13][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: Oc1cc(F)ccc1Br
Reactant: CC#COC1(F)C=C(F)C=CC1
Agent: C#CCOc1ccc(F)cc1Br
Product: C#CCOc1cc(F)ccc1Br
Yield: 87 %

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15 g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g (87%) 29f) 2-Bromo-4-fluoro-1-prop-2-ynyloxy-benzene
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:25])[N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:15](CC#N)[C:5]=3[C:4]=2[CH:3]=1.[C:26]([OH:29])(=[O:28])[CH3:27]>Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:25])[N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:15]([CH2:27][C:26]([OH:29])=[O:28])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: Cn1c2ccc(Cl)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Agent: Cl
Product: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 10 g (28 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in a mixture of 200 ml of concentrated hydrochloric acid and of 200 ml of acetic acid is heated at 100° C. for 4 h. The solution is concentrated under reduced pressure, the residue is taken up in 250 ml of water and the precipitate is collected by filtration. It is washed with water and dried under reduced pressure. 10.2 g (27 mmol) of solid are obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].O[C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][O:7][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: OCCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCc1ccc(OCc2ccc(Cl)cc2Cl)cc1

Procedure:
2.8 g. of sodium hydroxide in 10 ml. of water and 13.6 g. of 2,4-dichlorobenzyl alcohol are added to 8 g. of 4-hydroxyphenethyl alcohol in 80 ml. of ethanol. After refluxing the solution for 1.5 hours, the mixture is acidified with dilute sulfuric acid and extracted with methylene chloride. Drying and evaporation of the solvent yields the crude product at 100°-130° (air bath temperature)//0.02 torr by distillation with the use of a bulb tube. From cyclohexane, 14.5 g. of 4-(2,4-dichlorobenzyloxy)-phenethyl alcohol is obtained, m.p. 55°. The alcohol is converted, by 10 minutes of heating with thionyl chloride, into the [4-(β-chloroethyl)-phenyl]-(2,4-dichlorobenzyl)-ether and added to a solution of sodium imidazole, obtained by reacting 2 g. of imidazole with 1.04 g. of 80% strength sodium hydride - oil suspension in 30 ml. of dimethylformamide; the mixture is agitated for 6 hours at 100°-120° . The product is worked up as indicated in Example 56.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].Cl[C:19]1[C:24]([O:25][CH3:26])=[C:23]([CH2:27][O:28][CH3:29])[N:22]=[CH:21][N:20]=1>CN(C)C=O.ClCCl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:19]2[C:24]([O:25][CH3:26])=[C:23]([CH2:27][O:28][CH3:29])[N:22]=[CH:21][N:20]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: [H][H]
Reactant: COCc1ncnc(Cl)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COCc1ncnc(OCCc2ccc(C(C)(C)C)cc2)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
5.4 g (0.03 mol) of 2-(4-tert-butylphenyl)ethanol were added dropwise at 50° C. to a suspension of 1.2 g (0.03 mol) of sodium hydride (60% dispersion in oil) in 50 ml of dry dimethylformamide, and the mixture was stirred until the evolution of hydrogen had ceased. The mixture was cooled to 0° C., and 4.7 g (0.025 mol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine (Coll. Czechoslov. Chem. Commun. 33, 2266 (1968)) were added. The mixture was stirred for 1 hour at room temperature and for 2 hours at 100° C. After the solvent had been stripped off, the residue was taken up in dichloromethane/water, and the organic phase was dried and evaporated on a rotary evaporator. The crude product was chromatographed on silica gel using ethyl acetate. 3.8 g (46% of theory) of 4-[2-(4-tert-butylphenyl)ethoxy]-5 -methoxy-6 -methoxymethylpyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([S:7](=[O:10])(=[O:9])[NH2:8])[S:4][C:3]=1[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15].[C:17]1([O:23]C(Cl)=O)C=CC=CC=1.C(N(CC)CC)C.[CH3:34][C:35]1[N:40]=[C:39]([NH2:41])[CH:38]=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=1>C(#N)C>[C:14]([O:13][CH2:12][CH2:11][C:3]1[S:4][C:5]([S:7]([NH:8][C:17](=[O:23])[NH:41][C:39]2[CH:38]=[C:37]([C:42]([F:45])([F:43])[F:44])[CH:36]=[C:35]([CH3:34])[N:40]=2)(=[O:10])=[O:9])=[CH:6][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Reactant: Cc1cc(C(F)(F)F)cc(N)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OCCc1sc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)cc(C)n2)cc1C
Reaction time: 2 h
Yield: 177.2 %

Procedure:
To a solution of 0.235 g acetic acid 2-(3-methyl-5-sulfamoyl-thiophen-2-yl)-ethyl ester in 5 ml acetonitrile was added 0.188 g phenylchloroformate and 0.252 g triethylamine at 0° C. and the mixture was stirred at this temperature for 2 h. To the resulting suspension was added 0.220 g 6-methyl-4-trifluoromethyl-pyridin-2-ylamine and the mixture was heated to 60C for 18 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated. The residue was triturated with diethylether. The solid was collected by filtration to yield 0.736 g of the title compound as light yellow crystals. MS (ISN) M−H+=463.9
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4([NH:42]C(=O)OC(C)(C)C)[CH2:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH:25]5[CH2:30][O:29][CH2:28][CH2:27][O:26]5)=[O:24])[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[Cl:57]CCl>>[ClH:57].[NH2:42][C:38]1([C:35]2[CH:34]=[CH:33][C:32]([N:31]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([NH:22][C:23]([CH:25]6[CH2:30][O:29][CH2:28][CH2:27][O:26]6)=[O:24])[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:37][CH:36]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6COCCO6)c5)nc43)cc2)CCC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(NC(=O)C4COCCO4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(1,4-dioxan-2-ylcarbonyl)amino]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (38 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Dichloromethane (5 mL) and MP-carbonate (Argonaout technologies 2.91 mmol/g, 400 mg) were added. The mixture was stayed for 30 min. with occasional shaking then filtered. The filtrate was concentrated under reduced pressure. To a solution of the residue in dichloromethane (5 mL) and methanol (0.4 mL) was added hydrogen chloride in ethyl acetate (4 M, 0.072 mL) at room temperature. After being stirred for 10 min., the mixture was concentrated under reduced pressure. The resulting solid was suspended with ethyl acetate and filtered to give the product (24 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][S:10]C1C=CC(O)=CC=1>>[CH3:9][S:10][C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1ccc(O)cc1
Reactant: CSc1ccc(O)cc1
Product: CSc1cc(C)ccc1O
Temperature: 176 °C
Yield: 58.4 %

Procedure:
p-Cresol (1.2 g, 0.01 mole), para-(methylthio)phenol (3.0 g, 0.02 mole), and H ELZ-20 from Example 27 (1.0 g) were combined and heated at 176° C. for 14 hours. The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator. GC analysis indicated the presence of 2-methylthio-4-methylphenol (0.9 g, 56% yield).
Reaction SMILES: CNC=O.N([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])=C=S.IC>CO>[C:11]([OH:13])(=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(N=C=S)c1
Solvent: CI
Solvent: CO
Solvent: CNC=O
Product: O=C(O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 3-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h and concentrated the solvent and purified on silica gel to yield 3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoic acid. MS: MH+=417.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](F)[CH:3]=1.C(S)[CH2:11][S:12]([O-])(=O)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([S:12][CH3:11])[CH:3]=1
Reactant: O=S(=O)([O-])CCS
Reactant: Cc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Br)ccc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-1-methyl-benzene (3 mL, 26.3 mmol) in DMF (15 mL) was added MeSNa (1.84 g, 26.3 mmol). After the addition, the reaction mixture was stirred at 90° C. overnight. TLC (petroleum) showed the reaction was complete. Then the mixture was poured into aq. NaHCO3 (10 mL), extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over sodium sulfate and concentrated in vacuum. The residue was purified by a silica gel column chromatography (petroleum) to give 4-Bromo-1-methyl-2-methylsulfanyl-benzene (4 g, 68%) as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[CH:36]([NH2:38])[CH2:35][CH2:34]2>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:38][CH:36]2[C:37]4[C:33](=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][CH3:27])[CH2:34][CH2:35]2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: COc1cccc2c1C(N)CC2
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=482.5 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and rac-7-methoxy-indane-1-ylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH2:28])[CH:23]=[CH:22]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:16])[CH:23]=[CH:22]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and K2CO3 (1 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, then stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is crystallized from EtOAc/heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (62 mg, 17%) as a solid. MS: 365 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.82 (s, H), 6.55 (s, H) 6.90-7.41 (m, 4H), 7.49 (m, H), 8.26 (d, 2H), 8.57 (br, H), 8.96 (br, H). IC50=19 nM.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([Cl:41])[CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:38][C:37]1[CH:39]=[CH:40][C:34]([Br:33])=[CH:35][C:36]=1[Cl:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Reactant: Nc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2Cl)c2cnccc2n1C
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A degassed solution of 1-methyl-3-(nonafluorobutane-1-sulfonyloxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (500 mg, 0.99 mmol), 4-bromo-2-chloroaniline (246 mg, 1.19 mmol), Pd2dba3 (91 mg, 0.10 mmol), Xantphos (114 mg, 0.20 mmol) and DBU (352 μl, 2.48 mmol) in toluene (8 ml) was subjected to microwave irradiation at 120° C. for 5 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (100 ml). The resultant solution was washed with water (30 ml), dried (Na2SO4) and concentrated in vacuo to give an oil. The oil was purified by flash chromatography (Si-PPC, cyclohexane:ethyl acetate, gradient 90:10 to 0:100) to afford the title compound as a yellow solid (140 mg, 35%). 1H NMR (CDCl3, 400 MHz) 8.75 (d, J=1.0 Hz, 1H), 8.41 (d, J=6.1 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.19-7.27 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.99 (s, 3H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: NC(C)(C)C/C=C/C(N([C@H](CC1C=CC2C(=CC=CC=2)C=1)C([N:13]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH2:25][CH2:26]O)[CH3:14])=O)C)=O.ON1[C:46]2[CH:47]=CC=[CH:50][C:45]=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C([OH:67])C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]([NH:13][CH3:14])=[O:67])[C:25]1[CH:26]=[CH:47][CH:46]=[CH:45][CH:50]=1
Reactant: On1nnc2ccccc21
Reactant: CN(CCc1ccccc1OCCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide ##STR173## 2-(2-Benzyloxyphenyl)-N-methylacetamide ##STR174## 2-(2-Benzyloxyphenyl)acetic acid (15.0 g, 62 mmol) was dissolved in dichloromethane (270 ml) and N,N-dimethylformamide (70 ml). 1-Hydroxybenzotriazole (8.37 g, 62 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.89 g, 62 mmol) was added. The reaction mixture was stirred for 20 min. A 8.0M solution of methylamine in ethanol (38.8 ml, 310 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (500 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate solution (500 ml). The aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The remaining crystals were washed with a mixture of ethyl acetate/heptane 1:4 (100 ml). They were dried in vacuo. They were dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×500 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 10.24 g of 2-(2-benzyloxyphenyl)-N-methylacetamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Yield: 70.4 %

Procedure:
Using 4-bromobenzoic acid (0.50 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.54 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (0.70 g) was obtained.