Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1cnc(Cl)cn1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4C)nc3)C3CC3)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg, Intermediate 20), 2-chloro-5-methylpyrazine (15 mg) and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1.0 mL) is heated in a microwave oven for 30 min at 200° C. After removal of the solvent the residue is purified by HPLC(H2O/MeOH/TFA) to give the title compound. LC (method 3): tR=0.92 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.6) (0.43 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.46 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:19])[CH:17]=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:17](=[O:18])[CH:16]([OH:19])[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A mixture of 21.2 g (0.10 mol) of 2,4-di-tert-butylphenol (97%), 16.3 g (0.11 mol) of 50% aqueous glyoxylic acid and 0.05 g (0.26 mmol) of p-toluenesulfonic acid monohydrate in 30 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. Afterwards the reaction mixture is concentrated on a vacuum rotary evaporator. The residue is taken up in 80 ml of hexane and washed three times with water. The aqueous phases are separated in the separating funnel and further extracted with 30 ml of hexane. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. The residue yields 26.23 g (~100%) of analytically pure 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one in the form of a thick yellowish resin (compound (101), Table 1).
Reaction SMILES: Cl[CH:2]([C:14](=O)[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].C([O-])=[O:18].[Na+].C([O-])=O.[NH4+].C(=O)([O-])O.[Na+].[CH:30]([NH2:32])=[O:31]>>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2](=[O:18])[CH:14]([NH:32][CH:30]=[O:31])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Reactant: O=C[O-]
Reactant: NC=O
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Product: CN=C(NC#N)NCCSCC(=O)C(C)NC=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
In 2.5 ml of formamide were dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)ethyl]-N'-cyano-N"-methylguanidine, 136 mg of sodium formate and 320 mg of ammonium formate, and the solution was stirred at room temperature for 3 days. Then, 420 mg of sodium hydrogencarbonate was added to the solution and formamide was removed under reduced pressure, and the obtained residue was refined by silica gel column chromatography (developing solvent: chloroform/ethanol=5/1) to obtain 28 mg of a colorless oily product (the yield was 19%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](O)(=O)C.Br[N:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=O>C(Cl)(Cl)Cl>[CH:5]1[C:6]2[NH:14][C:15]3[C:8](=[CH:9][CH:18]=[CH:17][CH:16]=3)[O:7][C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: COc1ccccc1
Reactant: CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)Nc1ccccc1O2
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
Phenoxazine (2.00 g, 10.92 mmol), 4-bromoanisole (2.25 g, 12.03 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), t-Bu3P (0.067 g, 0.33 mmol), and t-BuONa (1.57 g, 16.34 mmol) were dissolved in toluene (100 ml), and the reaction mixture was refluxed for 15 hours and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was extracted with chloroform. The extracted solution was twice washed with a supersaturated sodium chloride solution and water (H2O), and the organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain a crude product, and the crude product was purified by silica gel column chromatography to yield 2.27 g (72%) of a compound where the N-position of phenoxazine was substituted by anisole. The compound (2.00 g, 6.91 mmol) was dissolved in chloroform (100 ml), and acetic acid (100 ml) was added thereto. N-bromosuccinimide (NBS) (2.70 g, 15.20 mmol) was added in small amounts at 0° C., and the reaction mixture was heated to room temperature and incubated at room temperature for 10 hours. After the reaction was terminated, the solvent was removed under reduced pressure, and the residue was extracted with chloroform. The extracted solution was twice washed with a supersaturated sodium chloride solution and water (H2O), and the organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain a crude product, and the crude product was purified by silica gel column chromatography to yield 2.62 g (85%) of a phenoxazine derivative compound substituted by a dibromo compound. The phenoxazine derivative compound (1.47 g, 3.29 mmol) was dissolved in tetrahydrofuran (100 ml), and n-butyllithium (4.6 ml, 7.36 mmol, 1.6 M solution) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.48 ml, 7.25 mmol) were gradually dropwise added thereto at −78° C. The reaction mixture was gradually heated to room temperature and incubated at room temperature for 15 hours. The reaction was terminated by the addition of water (H2O) (50 ml), and the resultant solution was extracted with chloroform. The extracted solution was twice washed with a supersaturated sodium chloride solution and water (H2O), and the organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain a crude product, and the crude product was purified by silica gel column chromatography to yield 1.16 g (65%) of the intermediate D.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5].[N:16]1([CH2:21][CH2:22][OH:23])[CH:20]=[CH:19][N:18]=[N:17]1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(CCl)c(F)c1
Reactant: OCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COCCn2ccnn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
816 mg (32.3 mmol) 95% Sodium hydride were given at −50° C. to a solution of 4.32 g (21.5 mmol) 1-allyloxy-3-fluoro-4-chloromethyl-benzene and 2.51 g (22.2 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 30 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 10 ml water added. The mixture was extracted twice with ethyl acetate, and the combined organic phases dried over Na2SO4. Solvents were removed in vacuum to yield 6.18 g 1-[2-(4-allyloxy-2-fluoro-benzyloxy)-ethyl]-1H-[1,2,3]triazole yellow oil that was used without further purification.
Reaction SMILES: ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:8][CH:9]([CH3:13])[C:10](Br)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:8][CH:9]([CH3:13])[C:10]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:11]
Reactant: Clc1ccccc1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To 200 ml of dichloromethane are added 23.7 g (0.176 M) of aluminium chloride. The mixture is cooled to 10° C. and 10 g (0.089 M) of chlorobenzene are added dropwise. The resulting mixture is stirred for one hour at 15° C. followed by dropwise addition of 9.2 ml (0.089 M) of 2-bromopropionyl bromide. The reaction medium is then stirred for 16 hours at room temperature. The reaction medium is then poured into an ice/water mixture. The organic phase is separated out by settling, washed twice with demineralised water and then dried over sodium sulfate. After evaporating under vacuum, an oil is obtained, which crystallises to give 21 g of 2-bromo-1-(4-chlorophenyl)propan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])(=[O:10])[CH3:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 13.5 parts of 1-(2-aminophenyl)ethanone, 12.1 parts of N,N-diethylethanamine and 72 parts of benzene are stirred and cooled at 5°-10° C. Then there is added dropwise a solution of 18.2 parts of trichloroacetyl chloride in 36 parts of benzene while still cooling at 1°-10° C. Upon completion, stirring at that temperature is continued for 30 minutes. The reaction mixture is filtered, the filter-cake is washed with benzene and the filtrate is evaporated. The solid residue is boiled in methanol. After cooling, the product is filtered off and dried, yielding 19 parts (68%) of N-(2-acetylphenyl)-2,2,2-trichloroacetamide; mp. 112.7° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and CuI (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].O>CS(C)=O>[F:20][C:21]1[CH:28]=[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reaction time: 8 h
Yield: 48.7 %

Procedure:
9.17 g (49.3 mmol) of tert-butyl piperazine-1-carboxylate and then 6.81 g (49.3 mmol) of potassium carbonate, respectively, are added to 7 g (49.3 mmol) of 2,4-difluorobenzaldehyde diluted in 60 ml of dimethylsulfoxide. The solution is carried at 60° C. for 8 hours and then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 7:3 cyclohexane/ethyl acetate) to yield 7.4 g (48%) of tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([N:29]3[CH2:35][C:34]4[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH2:30]3)=[N:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:6][C:5]([C:37]2[CH:38]=[CH:39][C:33]3[O:32][CH2:31][CH2:30][N:29]([C:23]4[C:22]5[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[N:26]=[CH:25][N:24]=4)[CH2:35][C:34]=3[CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Reactant: C[C@@H](CO)CS(=O)(=O)c1cc(Br)cnc1N
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)C[C@@H](C)CO)c5)cc4C3)ncnc2c1

Procedure:
Prepared according to the method of example 5 by using (2S)-3-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-2-methylpropan-1-ol (reagent preparation 41) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.42 (s, 1H), 8.34 (br, 1H), 8.07 (br, 1H), 7.89 (d, 1H), 7.44 (s, 1H), 7.35 (d, 1H), 7.08 (m, 2H), 6.94 (d, 1H), 4.96 (s, 2H), 4.34 (m, 2H), 4.14 (m, 2H), 3.84 (s, 3H), 3.41 (m, 2H), 3.31 (dd, 1H), 2.98 (dd, 1H), 2.12 (m, 1H), 0.99 (d, 3H); MS (EI) for C27H20N5O5S: 536 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][C:7]=1[C:8](O)=[O:9]>CN(C)C=O.C1C=CC=CC=1>[F:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(C(F)(F)F)c1F

Procedure:
30 ml of benzene, 17 ml of thionyl chloride and several drops of N,N-dimethylformamide were added to 8.5 g (0.0348 mole) of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid (VII), and the mixture was refluxed under heating for 3 hours. After the reaction, benzene and excess thionyl chloride were removed by evaporation under reduced pressure to obtain 2,4,5-trifluoro-3-trifluoromethylbenzoic acid chloride (VIII).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.F[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1B(O)O.[F-:49].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:49][C:44]1[CH:43]=[CH:42][C:41]([F:45])=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)=[O:29]
Reactant: OB(O)c1c(F)cccc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: [F-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Add trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (552 mg, 1.0 mmol), 2,6-difluorophenyl boronic acid (320 mg, 2.0 mmol), trans dichlorobis(triphenylphosphine)palladium II (70 mg, 0.1 mmol) and cesium fluoride (1.3 g, 8.6 mmol) to a 20 mL vial along with 8.0 mL degassed acetonitrile. Seal the vial with a septum and purge with nitrogen gas. Heat the mixture with stirring at 80° C. for three hours. Cool, filter and purify on an SCX column, eluting with 2N ammonia/methanol. The compound is further purified on a silica gel column, eluting with a 0-5% 2N ammonia in methanol/methylene chloride gradient. The yield is 260 mg (50%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:3]\[CH2:4][S:5][CH2:6][C@@H:7]([C:19]([OH:21])=[O:20])[NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][C:13](=[O:17])[O:14]CC.[Li+].[OH-].C(OCC)(=O)C.Cl>C1COCC1.O>[C:13]([CH2:12][CH2:11][NH:10][C:9](=[O:18])[NH:8][C@@H:7]([CH2:6][S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C:19]([OH:21])=[O:20])([OH:17])=[O:14]
Reactant: CCOC(=O)CCNC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)NCCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, Compound D of Example 6 (100 mg, 0.21 mmol) was dissolved in THF (10 mL). LiOH (500 mg, 20 mmol) in water (5 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture. The reaction mixture was acidified by 1 N HCl solution (pH=4.0). The organic portion was separated and dried over Na2SO4, concentrated and purified by HPLC (40 mg, 41%) to yield Compound G. 1H-NMR (500 MHz, MeOH-d4): δ 1.62 (bs, 6H), 1.69 (s, 3H), 1.70 (s, 3H), 1.99 (m, 2H), 2.08 (m, 6H), 2.51 (t, J=6.5, 2H), 2.79 (dd, J=7.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 8.1 Hz, 1H), 3.17 (dd, J=7.0, 13.0 Hz, 1H), 3.28 (dd, J=9.0, 15.0 Hz, 1H), 3.40 (t, J=6.5 Hz, 3H), 4.50 (dd, J=5.0, 6.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 16.1, 16.2, 17.8, 26.0, 27.4, 27.8, 30.5, 34.4, 35.7, 36.8, 40.8, 40.9, 54.1, 121.7, 125.2, 125.5, 132.1, 136.3, 140.5, 160.3, 175.1, 175.7; ES-MS: mass calcd for Chemical Formula: C22H36N2O5S 440.6. Found (M+Na) m/z 463.3.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>CC#N>[CH3:6][CH:5]([CH3:7])[C:4](=[O:8])[CH2:3][CH2:2][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)CCCl
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)C(=O)CCNc1ccccc1

Procedure:
A suspension of the crude 1-chloro-4-methylpentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHCO3 (210 g, 2.5 mol) in CH3CN (1000 mL) was heated at reflux overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with CH2Cl2, washed with 10% HCl solution (100 mL) and brine, dried over Na2SO4, filtered and concentrated to give the crude 4-methyl-1-(phenylamino)-pentan-3-one.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]([CH2:7]CCO)[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28]C([N+]([O-])=O)=CC=1)=[O:22].[CH:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1>C(Cl)Cl>[C:36]1([N:39]2[CH2:40][CH2:41][N:42]([C:21]([O:23][CH2:24][CH2:29][CH2:28][N:6]3[CH2:5][CH2:4][N:3]([CH3:7])[CH2:2][CH2:1]3)=[O:22])[CH2:43][CH2:44]2)[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCCN1CCNCC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
1-(3-Hydroxypropyl)-4-piperazine (0.63 g, 4.0 mmol) was dissolved in DCM (30 mL) and cooled to 0° C. DIPEA (1.39 mL, 8.0 mmol) and p-nitrophenyl chloroformate (0.80 g, 4.0 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then phenylpiperazine (0.61 mL, 4.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed sequentially with 1M aq Na2CO3 solution (4×100 mL), and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (30 mL) and stirred with solid Na2CO3 for 20 minutes, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (gradient eluting with acetonitrile in water, 5-45%) to give 3-(4-methyl-piperazin-1-yl)propyl 4-phenylpiperazine-1-carboxylate (148 mg, 11%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]([NH2:17])=[O:16])=[C:6]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](OC)=[O:26])=[CH:21][C:20]=1[CH3:29].[BH4-].[Li+].O.C(O)(=O)C>O1CCCC1>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:15]([NH2:17])=[O:16])=[C:20]([CH3:29])[CH:21]=1
Reactant: COC(=O)c1ccc(Nc2c(C(N)=O)cnc3cc(OC)c(OC)cc23)c(C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccc(CO)cc3C)c2cc1OC
Reaction time: 24 h
Yield: 43.5 %

Procedure:
6,7-Dimethoxy-4-(4-methoxycarbonyl-2-methylanilino)-3-quinolinecarboxamide (0.080 g, 0.20 mmol) was dissolved in tetrahydrofuran (25 ml, dried over 4 A molecular sieves). Lithium borohydride (0.15 mg, 6.8 mmol) was added. The mixture was stirred for 24 h and additional lithium borohydride (0.050 g, 2.2 mmol) was added. The reaction mixture was stirred for additional 25 h and then poured into a cooled mixture of water (20 ml) and acetic acid (0.5 ml). Acetic acid (2 ml) was added and the mixture was evaporated under reduced pressure. The residue was suspended in water, filtered and the precipitate was washed with water and re-crystallized from aqueous methanol to give the title compound (32 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[C-:11]#[N:12].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]#[N:12]
Reactant: Clc1ccc(CBr)c(Br)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cl)cc1Br
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A mixture of 2-bromo-1-(bromomethyl)-4-chlorobenzene (9.8 g; 34.5 mmol) and sodium cyanide (2.0 g; 41.4 mmol) in 15 mL of 95% ethanol and 2.5 mL water was stirred and heated to reflux. After 30 minutes, the solvent was evaporated and the residue was partitioned between 100 mL ether and 50 mL water. The organic layer was dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, washed with hexane, and air-dried on the filter to give 4.82 g of 2-(2-bromo-4-chlorophenyl)acetonitrile as a light yellow solid.