Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(CC(C2C=CC=CC=2)=O)ON=1.CN(CN(C)C)C.FC(F)(F)C(O)=O.NN.[CH3:32][C:33]1[CH:37]=[C:36]([CH:38]2[CH2:42][NH:41][N:40]=[C:39]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:35][N:34]=1.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[O:60])=[CH:54][CH:53]=1>ClCCl.C(O)(=O)C>[CH3:32][C:33]1[CH:37]=[C:36]([CH:38]2[CH2:42][N:41]([C:59]([NH:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][C:50]([F:49])([F:61])[F:62])=[CH:53][CH:54]=3)=[O:60])[N:40]=[C:39]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:35][N:34]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(C2CNN=C2c2ccccc2)on1
Agent: CN(C)CN(C)C
Agent: Cc1cc(CC(=O)c2ccccc2)on1
Agent: NN
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CN(C(=O)Nc3ccc(OC(F)(F)F)cc3)N=C2c2ccccc2)on1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
A mixture of 20 mL of dichloromethane, 2.01 g (10 mmol) of 2-(3-methyl-5-isoxazolyl)-1-phenylethanone and 1.12 g (11 mmol) of N,N,N',N',-tetramethyldiaminomethane was prepared and cooled to -15° C. and 1.25 g (11 mmol) of trifluoroacetic acid in 5 mL of dichloromethane was added with cooling and stirring. Stirring was continued for 5 min at about 0° C. and then the mixture was allowed to warm to ambient temperature and stir for another 1.75 hr. A proton NMR spectrum of the mixture was taken which indicated complete disappearance of the starting material. Anhydrous hydrazine (0.96 g, 30 mmol) was added and the mixture was allowed to react with stirring for 2 hr. A proton NMR spectrum of the mixture indicated complete conversion to 4,5-dihydro-4-(3-methyl-5-isoxazolyl)-3-phenyl-1H-pyrazole. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and filtered. 4-(Trifluoromethoxy)phenyl isocyanate (2.19 g, 10.8 mmol) was then added with stirring. The mixture was allowed to react for 1 hr and then 1 mL of acetic acid was added and the mixture was allowed to react for 5 min. It was then washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure. The resulting solid was extracted with boiling ether and air dried to obtain 3.1 g (72 percent of theory) of the title compound as a white solid melting at 195°-197° C.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1(C)C(C)=CC=CC=1>[Br-:23].[CH2:24]([P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reactant: CCCCBr
Solvent: Cc1ccccc1C
Product: CCCC[P+](c1ccc(C)cc1)(c1ccc(C)cc1)c1ccc(C)cc1
Product: [Br-]
Temperature: 45 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5 gms (0.0164 mole) of tri-p-tolyl phosphine and 24 gms of xylene. The slurry is heated to 45° C. then 2.7 gms (0.0197 mole) of 1-bromo butane is added. This reaction mass is heated to 50° C. and maintained at that temperature for 0.65 hour, then heated to 80C and maintained at that temperature for 16.08 hours, then heated to 100C and maintained at that temperature for -.97 hour. The salt is decanted and then vacuum dried. There is obtained 2.098 gms of an oily catalyst.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH2:15][C:16](=[O:23])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:20][C:19]([F:22])([F:21])[CH2:18][NH:17][C:16]([CH2:15][NH3+:14])=[O:23]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]CC(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
Trifluoracetic acid (23.4 ml) is added dropwise to a solution of [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid ter-butyl ester (3.89 g) in dichloromethane (75 ml). After 18 hours at room temperature, the reaction mixture is concentrated in vacuo. The crude oil is purified by crystallization in diethylether to yield (2,2,2-trifluoro-ethylcarbamoyl)methyl-ammonium trifluoroacetate (4.12 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([N:29]3[CH2:28][CH2:27][CH:26]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[CH2:31][CH2:30]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn(C2CCNCC2)nn1
Reactant: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(N2CCC(n3ccnn3)CC2)ncc1F
Yield: 34.3 %

Procedure:
A solution of the product of Step 1 (123 mg, 0.42 mmol), 4-(1H-1,2,3-triazol-1-yl)piperidine (94 mg, 0.50 mmol) and diisopropylethylamine (2 mL) was irradiated in 2-propanol (2 mL), in a microwave oven, at 150° C. for 2 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (0%-100%) to give the product (59 mg, 34%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[CH:23](OCC)=O.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][S:9]([NH:8][C:6]1[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]2[C:20](=[O:21])[CH:22]=[CH:23][O:1][C:2]=2[CH:7]=1)(=[O:11])=[O:10]
Reactant: CCOC=O
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
In 70 ml of toluene was suspended 3.4 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. 17 ml of ethyl formate was added thereto. Further, 3.4 g of sodium hydride (purity: 60%) was added thereto in portions in 20 minutes. The mixture was refluxed for 5 hours. The reaction mixture was introduced into 300 ml of ice water. The aqueous layer was separated and adjusted to pH 4 with 4N hydrochloric acid. The mixture was then extracted with two 100-ml portions of ethyl acetate. The extracts were combined and subjected to distillation under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of acetic acid. 1 ml of concentrated hydrochloric acid was added. The mixture was heated for 30 minutes at 50°-60° C. 200 ml of water was added thereto. The resulting mixture was extracted with 200 ml of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 2.28 g (yield: 65%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 216.7°-217 6° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH3:3].CN(C=O)C.C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]2[C:40]3[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[N:34]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[CH:33]=2)[C:29]([C:55]#[N:56])=[CH:28][N:27]=1>C1COCC1>[OH:10][CH:7]1[CH2:8][CH2:9][CH:4]([C@H:2]([NH:1][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:46])=[O:47])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:3])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: C[C@@H](N)C1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
4-((R)-1-aminoethyl)cyclohexanol (309.4 mg, 2.16 mmol) was dissolved in THF (10 mL) and DMF (4 mL) and stirred over molecular sieves for 10 minutes. Diisopropylethylamine (376.3 μL, 2.160 mmol) was added, followed by 2-chloro-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (516.1 mg, 1.080 mmol). The reaction mixture was stirred under nitrogen at ambient temperature for 18 hours. The molecular sieves was removed by filtration and washed with EtOAc. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-100% EtOAc/DCM) to afford the title compound as a yellow solid (558 mg, 88% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2NC(CC3CCOC3)=N[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[NH:36]([C:38](=O)[C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[NH2:37].O1CCC(CC(NN)=O)C1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4]([C:3]3[C:2]([CH3:1])=[CH:23][C:22]([CH3:24])=[C:21]([C:25]4[NH:26][C:38]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[N:36][N:37]=4)[CH:20]=3)=[O:5])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CN(C)C(=O)C(=O)NN
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(C(=O)N(C)C)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-hydrazinyl-N,N-dimethyl-2-oxoacetamide (compound 135.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 457 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.B.[Na]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 72 %

Procedure:
1.0 g of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature. The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96°-97° C.
Reaction SMILES: [I:1]CCCC.[OH:6][C:7]1(I)[CH:16]=[CH:15][CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([C:26]([CH3:28])=O)[CH3:25]>>[CH2:25]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:1])[C:10]([O:12][CH3:13])=[O:11])[CH2:24][CH2:26][CH3:28]
Reactant: CCCCI
Reactant: COC(=O)C1=CC=CC(O)(I)C1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cc(C(=O)OC)ccc1I
Temperature: 85 °C
Yield: 99 %

Procedure:
21.5 mL (0.189 mol, 1.5 eq) of 1-iodobutane are added to a solution of 35.03 g (0.126 mol, 1 eq) of methyl 3-hydroxy-3-iodobenzoate in 350 ml of methyl ethyl ketone in the presence of 52.24 g (0.378 mol, 3 eq) of potassium carbonate. The reaction medium is heated at 85° C. for 2 hours. The solid is filtered off and the solvent is evaporated off. The solid obtained is washed with heptane to give 41.78 g of methyl 3-butoxy-4-iodobenzoate in the form of white crystals. Yield=99%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:15]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)nc1
Yield: 100 %

Procedure:
6-Aminonicotinic acid (1.06 g, 7.7 mmol) was suspended with stirring in anhydrous methanol (50 ml), and thionyl chloride (0.55 ml, 7.7 mmol) was added dropwise. The suspension was refluxed to a clear solution over 15 hours. The solvent was evaporated in vacuo and the residue taken up in water (20 ml). The solution was raised to pH 9 (sat. Na2CO3), extracted with chloroform, and dried over MgSO4. Evaporation of the chloroform gave 1.23 g (100%) product as white
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:13]([C:3]3[CH:4]=[N:5][N:6]([C:7]4[N:8]=[CH:9][CH:10]=[CH:11][N:12]=4)[C:2]=3[Cl:1])=[O:15])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: O=C(O)c1cnn(-c2ncccn2)c1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cnn(-c2ncccn2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-adamantan-1-ylmethan-amine (36 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 18 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo to give a reddish/brown oil. Purification by silica gel column chromatography (gradient from 90% EtOAc/hexane to EtOAc) affords the title compound as a light reddish/brown solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (2H, d, J 4.8), 8.28 (1H, s), 7.41 (1H, t, J 4.8), 6.47 (1H, bs), 3.18 (2H, d, J 6), 2.01 (3H, s), 1.69 (6H, m), 1.58 (6H, s). MS (M+1)=372.19; RT=1.31 min. *IC50.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([OH:19])[CH2:17][OH:18])=[N:14][CH:15]=1)[CH3:9].[S:20](Cl)(Cl)=[O:21]>ClCCl>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:17][O:18][S:20](=[O:21])[O:19]2)=[N:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C(O)CO)nc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C2COS(=O)O2)nc1
Reaction time: 1 h

Procedure:
4.98 mL (0.0387 mol) triethylamine was added to a solution of 3 g (0.017 mol) 1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol dissolved in 60 mL dichloromethane at 0-5° C. To this 1.43 mL (0.019 mol) thionyl chloride was added drop wise in 15 min. and stirring was continued for 1 hr. Reaction mixture was quenched with 10% sodium bicarbonate solution. Product was extracted with dichloromethane, which was concentrated in vacuo to obtain titled product. Yield of the product was 3.44 g (90%).
Reaction SMILES: [CH2:1]([CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.C(NCC)C.Cl>C(OCC)(=O)C.O>[CH2:12]=[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCNCC
Product: C=C(Cc1ccccc1)C(=O)O
Yield: 89.8 %

Procedure:
A solution of benzylmalonic acid (20.0 g, 0.103 mol, 1 eq) and paraformaldehyde (4.94 g, 0.164 mol, 1.6 eq) in ethyl acetate (150 mL) was cooled (0° C.) and treated with diethylamine (10.65 mL, 0.103 mol, 1 eq) drop wise, keeping the reaction temperature below 20° C. (see FIG. 6). The reaction was then warmed to reflux for 90 min and cooled again on ice. The homogeneous solution was treated with water (20 mL) and concentrated aqueous HCl (12N) (9.0 mL, 0.108 mol) drop wise, keeping the reaction temperature below 10° C. The phases were then separated. The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum giving compound 17 as a white solid (15 g, 90%). Rf 0.46 (hexane/EtOAc=7:3). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 5H), 6.42 (s, 1H), 5.62 (s, 1H), 3.67 (s, 2H). [M−H]− 161.0: tR=2.53 min; purity: 99%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=3)=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:42](O)(C(F)(F)F)=[O:43]>C(#N)C.O>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[CH:8]=[CH:9][N:10]=[C:5]([C:3](=[O:4])[NH:2][CH2:1][CH2:42][OH:43])[CH:6]=3)=[CH:13][CH:14]=2)=[O:20])=[CH:27][C:26]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Sorafenib derivative S-6: S-5 (180 mg; 0.30 mmol) was dissolved in acetonitrile (3 ml), and a solution of N,N,N′,N′-tetramethyl-O—(N-succimidyl)uronium tetrafluoroborate (TSTU) (99 mg; 0.32 mmol) in acetonitrile (3 ml) was added, and N,N-diisopropylethylamine (67 μl; 0.37 mmol) was added. HPLC shows complete reaction after 10 min. 0.1% TFA in water (2 ml) is added, and the mixture is purified preparatively HLPC. S-6 is obtained as “off-white” solid substance (163 mg; 0.24 mmol; 78%). MS: M+H=692.1368; calculated for C30H25ClF3N5O9: 692.1371.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1>C(OCC)(=O)C.C(O)C>[NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(N)Cc1ncccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(N)Cc1ncccc1N
Yield: 100.1 %

Procedure:
2-aminopropyl-3-nitropyridine (171)(6.3 g, 35 mmol) is dissolved in 100 mL 1/1 ethyl acetate/ethanol in a Parr shaker bottle. Nitrogen is bubbled through the solution for 2 minutes followed by the addition of 10% Pd/C (500 mg). The suspension is hydrogenated on a Parr apparatus under 40 psi of H2 until hydrogen uptake ceased. The suspension is filtered through Celite and the solvent evaporated in vacuo to afford 5.3 g of the 2-aminopropyl-3-aminopyridine (182).
Reaction SMILES: C1(C(=[N:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C.C([O-])(O)=O.[Na+]>[NH2:14][C:15]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC)(CC)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(N)(CC)CC
Temperature: 0 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
A solution of ethyl 2-[(diphenylmethylene)amino]-2-ethylbutanoate (20.79 g, 64.3 mmol), prepared in the previous step, in 200 mL of diethyl ether was cooled under nitrogen to ice-bath temperature. 1 N HCl (96 mL, 96.0 mmol) was added dropwise over 45 min. After the addition the ice-bath was removed and the stirring continued for 15 h. The diethyl ether layer was separated and the aqueous layer was extracted two times with 50 mL of methylene chloride. The methylene chloride extracts were extracted two times with 40 mL of 2 N HCl. The aqueous layers were combined and concentrated under reduced pressure to give an oil. The oil was taken up in 200 mL of saturated NaHCO3 and stirred for 30 min. The aqueous layer was then extracted five times with methylene chloride. The organic extracts were dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give ethyl 2-amino-2-ethylbutanoate (9.3799 g, 92%) as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-])=O)[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Sn](Cl)Cl.O>CN(C)C=O>[NH2:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 205 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxy-5-nitrobenzoate (2.00 g, 7.25 mmol) in N,N-dimethylformamide (36 mL) was slowly added tin(II) chloride dehydrate (5.50 g, 24.4 mmol). The mixture was stirred at ambient temperature. After 10 min, water was added, and organics were extracted using ethyl acetate (5×). Combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→85% dichloromethane/methanol) gave the title compound (3.657 g, 50% purity). LC-MS [M]=246.1.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:31][CH2:30][C@H:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:35])[CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:27][CH2:28][C@H:29]([C:32]([NH2:37])=[O:33])[CH2:30][CH2:31]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:35])[CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(N)=O)CC1
Reaction time: 2 h

Procedure:
To a flask containing racemic trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid (25 mg, 0.051 mmol) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25.1 mg, 0.066 mmol) and ammonium chloride (10.9 mg, 0.203 mmol). DMF (1 mL) and N,N-diisopropylethylamine (0.089 mL, 0.507 mmol) were added and the reaction was sealed and stirred for 2 hours. Methanol (0.1 mL) was then added to quench the reaction and the resulting solution was filtered. The filtrate was purified by reversed phase HPLC (10-100% acetonitrile/water with 0.1% TFA). The fractions containing desired product were pooled, frozen and concentrated to dryness on a lyophilizer to afford trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide. MS ESI calc'd. for C27H34N5O2S [M+H]+ 492. found 492. 1H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.49 (s, 1H), 8.30 (d, J=6.4 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.15 (s, 1H), 7.04 (d, J=6.4 Hz, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 5.84-5.30 (m, 1H), 2.43 (s, 3H), 2.30-2.15 (m, 1H), 2.07-1.87 (m, 4H), 1.87-1.67 (m, 3H), 1.54-1.42 (m, 1H), 1.42-1.18 (m, 6H), 1.12-0.93 (m, 3H), 0.79 (t, J=7.3 Hz, 3H) ppm. rhSyk=+++.