Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]=O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)c(Cl)c1
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(Cl)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (4.497 mmol) and 3-(3-chloro-4-trifluoromethyl-phenyl)-propionaldehyde (1.064 g; 4.497 mmol) afforded 8-[2-(3-chloro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.81 min.; [M+H]+=483.73 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21](Br)([CH3:23])[CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]([CH3:23])[CH3:22]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: CC(C)Br
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C(C)C

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isopropyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-propyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][C:5]2=1.[H-].[Na+].Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[CH:27][CH:26]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[CH:29][CH:30]=1)[C:6]1[CH2:11][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CC1CCCc2c([nH]c3ccc(F)cc23)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC1CCCc2c(n(Cc3ccc(-n4ccnc4)cc3)c3ccc(F)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of 122 mg of 2-fluoro- 5,6,7,8,9,10-hexahydrocyclohept[b]indole-7-acetic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 102 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 160 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluited HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, washed with acetone and dried, yields 116 mg of the title compound m.p. 237° C.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56](O)=[O:57])[CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>C1COCC1>[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH:63][C:56]([C:52]1[CH:51]=[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:55]=[CH:54][CH:53]=1)=[O:57]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (1.0 g, 2.74 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) followed by N,N-dimethylethylenediamine (0.29 g, 3.29 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[CH2:9]1[O:8][C:7]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:23]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1COC(c2ccco2)(c2ccco2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluoro benzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 7.77 (dd, J=1.95, 0.98 Hz, 2H), 7.66 (dd, J=8.3, 1.95 Hz, 1H), 7.59 (dd, J=7.32, 2.44 Hz, 1H), 7.45 (dd, JHF=JHH=8.79 Hz, 1H), 7.33-7.36 (m, 1H), 7.32 (d, J=8.79 Hz, 1H), 6.89 (d, J=2.44 Hz, 1H), 6.51 (dd, J=3.42, 1.95 Hz, 2H), 6.27 (dd, J=3.42, 0.98 Hz, 2H), 4.17 (s, 2H); MS (ESI) m/z 422/424 ([M−H]−); Anal. calcd for C23H15ClFNO4: C: 65.18; H: 3.57; N: 3.30. Found: C: 64.16; H: 3.66; N: 2.78.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:26]([N:11]1[CH2:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC1(c2cccc(Br)c2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of 28.2 g (81.4 mmol) of 4-(3-bromophenyl)-piperidin-4-ol in 600 ml of toluene was treated with 30 g (157 mmol) of p-toluenesulphonic acid monohydrate and heated to reflux on a water separator for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3 N sodium hydroxide solution. Thereafter, it was firstly extracted three times with 500 ml of methylene chloride. The combined organic phases were washed three times with 200 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 9.5 g (36% of theory) of 1-benzyl-4-(3-bromophenyl)-1,2,3,6-tetrahydro-pyridine as a light yellow oil; MS: 327, 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[O:7])=[CH:4][CH:3]=1.O.C(OCC)C.[BrH:24]>>[Br:24][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(NCCCCCCO)c1ccc(Cl)cc1
Reactant: Br
Solvent: CCOCC
Solvent: O
Product: O=C(NCCCCCCBr)c1ccc(Cl)cc1

Procedure:
6-(4-Chlorobenzoylamino)hexan-1-ol (17.0 g) was refluxed in 48% hydrobromic acid (260 ml) for 2.5 h. The mixture was cooled and added to water (450 ml) and diethyl ether (450 ml). The organic layer was washed with saturated sodium bicarbonate (450 ml) and brine (450 ml) and was dried over magnesium sulfate. Evaporation followed by recrystallisation from diethyl ether gave 1-bromo-6-(4-chlorobenzoylamino)hexane (8.6 g). 1H-NMR (CDCl3) δ 1.3-2.0 (8H, m), 3.35-3.55 (4H, m), 6.15 (1H, bs), 7.40 (2H, m) and 7.70 (2H, m).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](O)([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C(=O)OC)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-hydroxypropanoate (42b) (130 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol) and a spoon of sodium sulfate, in anhydrous toluene (3 mL), was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was successively washed with a saturated solution of sodium bicarbonate (2×5 mL) and brine (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (42c) (114 mg, 0.35 mmol, 93%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(Br)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
2,6-Dibromopyridine (0.47 g, 2.0 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.69 g, 3.0 mmol) and potassium phosphate (0.85 g, 4.0 mmol) were dissolved in N,N-dimethylformamide (10 ml) and degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was added then the mixture heated at 80° C. for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (200 ml) and extracted into ethyl acetate (2×150 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%) gave 2-(6-bromopyridin-2-yl)benzonitrile (0.518 g, 100%) as a waxy solid: δH (360 MHz, CDCl3) 7.53-7.57 (2H, m), 7.68-7.72 (2H, m), 7.80 (1H, d, J 8), 7.86-7.90 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl>C(Cl)Cl>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture consisting of 2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid (1-38, 10 mmol), 4-t-butylbenzylamine (12 mmol) and EDC (12 mmol) in CH2Cl2 (20 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated. the residue was purified by flash column chromatography on silica gel using EtOAc:hexanes as eluant to obtain N-(4-tert-butylbenzyl)-2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionamide (1-51, KMJ-372) having following physicochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH2:13])[CH3:12]>C(Cl)Cl>[CH2:11]([NH:13][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: CCN
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Product: CCNC(=O)c1ccccc1F
Yield: 87.8 %

Procedure:
2-Fluorobenzoyl chloride (2 g, 12.6 mmol) and 70% aq ethyl amine (1.78 g, 27.7 mmol) were combined in CH2Cl2 according to General Method E1, and kugelrohr distilled to give 1.85 g of N-ethyl-2-fluorobenzamide as a colorless oil, an 87% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[I:28]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[C:6]([I:28])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(I)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 32.4 %

Procedure:
A solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one (0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) in dichloroethane, containing dichloroacetic acid (0.1 mL) was heated to reflux for 6 h under argon atmosphere. After the removal of the solvents under reduced pressure, the residue was partitioned between, dichloromethane (20 mL) and 5% sod. sulphite (10 mL). The organic phase was washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (25% EtOAc in hexane) to afford the title compound (0.125 g, 32%) as a pale yellow powder: 1H NMR (CDCl3/400 MHz) δ7.68 (m, 1H), 7.46 (m, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 6.85 (m, 1H), 5.23 (s, 2H), and 2.38 (s, 3H); 19F NMR (CDCl3) δ −109.15 (m), −112.95 (m), −118.50 (m); ES-HRMS m/z 567.9014 (M+H C19H12NO2F4BrI requires 567.9027).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C=O)C.CO>[Br:20][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[C:7](=[N:8][C:3]([NH2:2])=[N:4][CH:5]=3)[N:9]([CH3:21])[N:10]=2)[CH:17]=[C:16]([F:18])[C:15]=1[O:19][CH2:31][CH2:30][O:29][CH3:28]
Reactant: COCCBr
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1c(F)cc(-c2nn(C)c3nc(N)ncc23)cc1Br
Temperature: 120 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in DMF (1 ml) then treated with K2CO3 (24 mg, 0.18 mmol) and 2-bromoethyl methyl ether (7.5 μL, 0.08 mmol). The reaction mixture is heated at 120° C. for 3 hours then cooled to room temperature, diluted with MeOH and concentrated in vacuo. The crude residue is dry loaded onto silica and purification by flash chromatography on silica eluting with iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) affords the title compound as an off-white soild.
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. 1H-NMR (400 MHz, CDCl3) δ value: 3.78(3H,s), 6.84(1H,s), 6.85(1H,d), 7.28(1H,s), 7.46(1H,d)ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH:21]=[CH:22][C:23]=1[CH3:24].[C:33](Cl)(Cl)=[O:34]>C(=S)=S>[CH3:31][C:28]1[C:33](=[O:34])[C:30]2[C:25](=[CH:26][C:27]=1[CH3:32])[C:20]1[C:21](=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=1)[CH:29]=2
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(-c2ccc(C)c(C)c2)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: S=C=S
Product: CC1=C(C)C(=O)C2=Cc3cc(C)c(C)cc3C2=C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
35.6 g of anhydrous aluminum chloride are added in portions to a solution of 20 g of biphenyl according to (a) and 14 g of phosgene in 130 ml of carbon disulfide at -10° C. to 0° C. in the course of 2 hours. After stirring at room temperature for 15 hours, the mixture is refluxed for 2 hours, poured onto ice-water and extracted with 1.5 l of chloroform. The residue from the organic phase (22.9 g) is separated by column chromatography on silica gel. Elution with methylene chloride/toluene=13:7 gives 9.8 g of 1,2,6,7-tetramethyl-fluorenone (Rf value 0.62) and 10.04 g of 2,3,6,7-tetramethyl-fluorenone (Rf value 0.41).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:30])[C:14]=2[C:18](=[O:29])[NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[N:9]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:13]1[C:14]([C:18](=[O:29])[NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]([F:27])([F:28])[CH2:23][CH2:22]2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:17]=[CH:16]2
Reactant: CCOC(=O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 3-{6-Chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-ylamino}-propionic acid ethyl ester (80 mg, 0.17 mmol, 1.00 eq) in THF (8.00 mL, 100 V) and Water (2.00 mL, 25 V) was added Lithium Hydroxide Monohydrate (14.72 mg, 0.35 mmol, 2.00 eq). The reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated under vacuum. The aqueous solution was adjusted to pH 2 and then extracted with ethyl acetate and combined organic layer was collected and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. The crude was purified by preparative HPLC to afford the title compound (35 mg, 0.08 mmol, 45.3%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (t, J=6.01 Hz, 1H), 7.60 (d, J=9.22 Hz, 1H), 7.46-7.52 (m, 2H), 7.31-7.33 (m, 1H), 6.84 (d, J=9.24 Hz, 1H), 3.57 (q, J=6.43 Hz, 2H), 3.22 (t, J=6.40 Hz, 2H), 2.54-2.57 (m, 2H), 2.03-2.00 (m, 2H), 1.72-1.89 (m, 5H), 1.22-1.31 (m, 2H). m/z: 426.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[I:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:1][C:2]3[CH:3]=[C:4]([CH2:5][N:6]4[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]4)[CH:13]=[CH:14][C:15]=3[N:16]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CN1CCN(Cc2ccc(N)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
A mixture of 1-(3,4-diaminobenzyl)-4-methylpiperazine (10 mmol), 3-iodo-4-methylbenzoic acid (2.6 g, 10 mmol), EDCI (11 mmol), and HOBt (11 mmol) in dry DMF (25 mL) was stirred at ambient temperature for 24 hrs. The mixture was then evaporated in vacuo and the crude residue was dissolved in CH2Cl2 (100 mL) was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue obtained was dissolved in AcOH (30 mL) and heated at reflux for 3 hrs. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to give a yellow solid (1.35 g, 30.3%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1H, s), 7.94-7.97 (1H, d, J=9.0 Hz), 7.53-7.56 (1H, d, J=9.0 Hz), 7.52-7.55 (1H, d, J=9.0 Hz), 7.30 (1H, s), 7.20-7.23 (1H, d, J=9.0 Hz), 3.60 (2H, s), 2.54 (8H, brs), 2.45 (3H, s), 2.32 (3H, s).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@H:25]([OH:36])[C:26]1[CH:31]=[CH:30][C:29]([Sn](C)(C)C)=[CH:28][CH:27]=1)=[O:22].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.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]>[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:2]2[S:6][C:5]([CH:7]3[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)[OH:36])=[O:22]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 80 °C
Reaction time: 70 h
Yield: 46.5 %

Procedure:
To a stirred solution of tert-butyl 2-(5-bromothiophen-2-yl)pyrrolidine-1-carboxylate (0.750 g, 2.26 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (1.0 g, 2.26 mmol), and tri(furan-2-yl)phosphine (105 mg, 0.452 mmol) in N-Methyl-2-pyrrolidone (10 mL) degassed with nitrogen is added Pd2(dba)3 (207 mg, 0.226 mmol). The reaction mixture is heated to 80° C. for 5 hours then left at ambient 70 hours. Reaction mixture partitioned between ethyl acetate (100 mL) and water (100 mL). Organic phase is isolated and concentrated in vacuo to give the crude material, which is purified by column chromatography on silica gel eluting in 0-100% ethyl acetate in heptane to give the title compound (559 mg): 1H-NMR (400 MHz, CDCl3) δ 1.32-1.52 (m, 9H), 1.89-2.15 (m, 3H), 2.21-2.37 (m, 1H), 2.59-2.78 (m, 1H), 3.40-3.66 (m, 2H), 4.25-4.38 (m, 1H), 4.43-4.49 (m, 0.5H), 4.54-4.62 (m, 1H), 4.66-4.73 (m, 0.5H), 5.01-5.25 (m, 2H), 5.89 (s, 1H), 6.83 (bs, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.5 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H). m/z (CI) M-boc+H 431.0.