Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[O:13].Br[CH2:15][C:16]#[C:17][CH2:18][CH3:19].[Cl-:20].[NH4+]>CN(C=O)C.CCCCCC>[Cl:20][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][C:4](=[O:13])[N:3]2[CH2:15][C:16]#[C:17][CH2:18][CH3:19]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: [Cl-]
Reactant: CCC#CCBr
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCC#CCn1c(=O)ccc2c(Cl)cccc21
Temperature: 0 °C

Procedure:
To a suspension of NaH (60% in mineral oil, 700 mg) in dry DMF (100 ml) at 0° C. was added the preceding quinolinone (2.05 g) and the mixture was stirred at 0° C. for one half hour. To the resulting suspension was added 1-bromo-2-pentyne (1.6 g) dropwise. The resulting mixture was kept at 0° C. for one half hour and poured into saturated aqueous ammonium chloride (200 ml). The aqueous suspension was extracted with ether (3×100 ml), the combined ether layers washed with brine and dried, yielding the crude product. Trituration with hexane yielded the product as a yellow solid (1 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([O:46][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCO
Product: CCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octanol, mp 56°-58° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: Nc1ccnn1-c1ccc(F)cc1
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1ccc(F)cc1

Procedure:
5-Amino-1-(4-fluorophenyl)pyrazole HCl (21 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 20.76 g. product. mp 162°-164°
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][O:11][C:4]1[N:3]=[C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Br)n1
Reactant: CC(=O)Nc1ccccc1
Product: COc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 93.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-6-methoxy-3-nitropyridine (116 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow solid (112 mg, 94%). mp 114-116° C. 1H NMR (DMSO) δ 2.56 (s, 3 H), 3.76 (s, 3 H), 6.85 (d, J=8.6 Hz, 1 H), 7.53-7.68 (m, 5 H), 8.12 (d, J=8.6 Hz, 1 H). 13C NMR δ 13.8, 53.4, 107.7, 122.9, 127.0, 128.0, 128.4, 129.2, 132.6, 144.1, 150.3, 161.1. HRMS (FAB): cal. for C14H14N3O [M-FH+]: 240.1237; found: 240.1234.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[H][H]>CC(O)=O.CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:6]2[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)=[CH:18][C:19]=1[S:26]([F:30])([F:31])([F:27])([F:28])[F:29]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(N)c(S(F)(F)(F)(F)F)c2)cc1C
Yield: 95.3 %

Procedure:
3.80 g of methyl 5-methanesulfonyl-4-(4-nitro-3-pentafluorosulfanylphenoxy)-2-methyl-benzoate were dissolved in 30 ml of HOAc and 30 ml of MeOH, 200 mg of Pd/C (10%) were added, and hydrogenation was carried out under a pressure of 6 bar of hydrogen for 24 h. Since reaction was still incomplete, a further 300 mg of Pd/C (10%), 30 ml of HOAc and 30 ml of MeOH was added, and hydrogenation was continued under a pressure of 6 bar of hydrogen for 24 h. The catalyst was then filtered off and the solvents were removed in vacuo. 3.4 g of a pale gray solid were obtained, mp 175° C. (with decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1)#[C:2][CH2:3][CH3:4].[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O:24][NH2:25])(=[O:23])=[O:22].C(OCC)C>ClCCl>[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[NH2:25][N+:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:1]#[C:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CCC#Cc1cc(OC)ccn1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC#Cc1cc(OC)cc[n+]1N
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reaction time: 1 h

Procedure:
To a solution of the obtained 2-(1-butynyl)-4-methoxypyridine (10.0 g) in dichloromethane (100 mL) there was added dropwise a solution of O-mesitylenesulfonylhydroxyamine (16.0 g) in dichloromethane (100 mL) at 0° C., and the mixture was stirred for 1 hour. Diethyl ether (250 mL) was added to the reaction mixture, and the precipitated solid was suction filtered and dried to obtain N-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate as a white salt (20.7 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccccc5F)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-fluorophenol (0.163 ml, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was heated to 70° C. After 1 h, the temperature was increased to 90° C. After 4 h, the reaction was cooled to RT and stirred overnight. The reaction was then cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.036 g, 0.096 mmol, 38% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.52 (1H, d, J=8.8 Hz), 8.12 (1H, dd, J=7.6, 1.4 Hz), 7.74-7.89 (1H, m), 7.36-7.66 (6H, m), 6.85-6.99 (2H, m), 3.32-3.36 (2H, m), 2.43 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 374.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12]([C:14]3[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=3[F:20])=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:25].[OH-]>C(Cl)Cl.C1COCC1>[NH2:25][S:21]([C:16]1[CH:17]=[CH:18][C:19]([F:20])=[C:14]([CH:15]=1)[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=1)=[O:13])(=[O:23])=[O:22]
Reactant: [NH4+]
Reactant: O=C(Nc1nnc(C2CCCC2)s1)c1cc(S(=O)(=O)Cl)ccc1F
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)c(C(=O)Nc2nnc(C3CCCC3)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a 20 ml scintillation vial was added 3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride (190 mg, 0.488 mmol) in a mixed solvent (DCM/THF=3 mL/1 mL). To this was added 1 ml of 7M NH4OH(NH3 28-30% w/w) . The reaction mixture was stirred vigorously at room temperature for two hours. After consumption of the starting material, the reaction solution was concentrated with a rotary evaporator. The product was dissolved with 1.0 mL of DMSO, was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 1% B to 99% B in 8.5 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-(aminosulfonyl)-N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (amount 33 mg, 18.2%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.BrC[CH2:28][CH2:29][Cl:30].[C:31](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:30][CH:29]([CH3:28])[CH2:31][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: ClCCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)Cl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (5 g), 1-bromo-3-chloropropane (7.4 ml) and potassium carbonate (20.6 g) were stirred in DMF (175 ml) at 50° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 70-80% ethyl acetate/hexane gave 3-[6-(2-chloropropoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (3.28 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.14 (s, 3H), 2.22 (m, 2H), 2.85 (m, 1H), 3.81 (t, 2H), 4.23 (m, 2H), 7.52 (m, 2H), 7.60 (s, 1H), 7.74 (d, 1H), 7.84 (s, 1H), 7.90 (d, 1H), 8.20 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 412.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)[NH:6]2
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Yield: 64 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl bromopyruvate (0.36 mL) and N,N-dimethylacetamide (14 ml) was stirred at 100° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (403 mg, yield 64%) as pale-brown crystals. MS:462 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(OCC)(=O)C.[ClH:22]>CO.O1CCOCC1.[Pd]>[ClH:22].[ClH:22].[CH3:1][N:2]([CH3:15])[S:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Nc1ccc(C#N)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Nc1ccc(CN)cn1

Procedure:
A solution of 6-(dimethylaminosulfonylamino)-3-cyanopyridine (250 mg, 1.1 mmol) in a mixture of MeOH (25 mL) and 4 N HCl in dioxane (1 mL) was hydrogenated over 10% Pd/C catalyst using a continuous flow hydrogenation apparatus (conditions: flow rate 1.0 mL/minute, 25° C., 1 atmosphere). The reaction was monitored by TLC (ethyl acetate). The methanol was concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]1([NH2:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:13]=[C:14]1[NH:23][C:22]2[N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH:28]=O)[CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15]1>>[C:1]1([N:12]2[CH2:17][CH2:22][N:21]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:20]3[N:21]=[C:22]4[C:17]([CH2:16][CH2:15][C:14](=[O:13])[NH:23]4)=[CH:18][CH:19]=3)[CH2:20][CH2:19]2)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: Nc1cccc2c1CCCCC2
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4CCCCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (0.178 g) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound as the hydrochloride salt (0.109 g). MS: APCI: M+1: 449.3 (Exact Mass: 448.26).
Reaction SMILES: C([Li])CCC.C(S)CC.[CH2:10]=[CH:11][CH2:12][S:13](=O)(=O)[S:14]/[CH:15]=[CH:16]/[CH2:17][S:18](=[O:23])(=[O:22])[CH2:19][CH:20]=[CH2:21]>O1CCCC1>[CH3:10][CH2:11][CH2:12][S:13][S:14]/[CH:15]=[CH:16]/[CH2:17][S:18](=[O:23])(=[O:22])[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCS(=O)(=O)C/C=C/SS(=O)(=O)CC=C
Agent: CCCS
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCS(=O)(=O)C/C=C/SSCCC
Temperature: 0 °C
Yield: 97 %

Procedure:
n-Butyllithium (75.5 μL, 0.106 m. mole) was added to a solution of 1-propane thiol (8.66 mg, 0.114 m. mole) in dry tetrahydrofuran (1.5 ml) under Argon with stirring at 0° C. This solution was added dropwise to a solution of (E)-4,5,9-trithiadodeca-1,6,11-triene 4,4,9,9-tetraoxide (30 mg, 1.106 m. mole) in tetrahydrofuran (5 ml) at -20° C. with stirring under Argon. The reaction mixture was stirred at -20° C. for 15 minutes, allowed to warm to room temperature and quenched by the addition of a saturated solution of ammonium chloride (3.0 ml) and methylene chloride (15 ml). The organic layer is separated, washed with water (5 ml), dried (magnesium sulfate) and concentrated under vacuum to give 26 mg of (E)-4,5,9-trithiadodeca-6,11-diene 9,9-dioxide product (97% yield) characterized by IR, Proton and Carbon 13 NMR spectroscopy.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5].NC(N)=[S:20].Cl.[OH-].[Na+]>O.C(O)(=O)C>[SH:20][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73.9 g (0.24 mol) of 2-bromo-4-(4-clorophenyl)nicotinic acid and 22.0 g (0.29 mol) of thiourea were weighed, and 100 ml of 5% HCl aqueous solution and 150 ml of acetic acid were added thereto. The resultant mixture was stirred at 100° C. for 2 hours, and was poured into water. Thereafter, 400 ml of 50% sodium hydroxide aqueous solution was added to the resultant mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then acidified with 20% HCl aqueous solution, and the crystal thus precipitated was filtrated out and was washed with water. The washed crystal was then dried to obtain a crude crystal of 2-mercapto-4-(4-chlorophenyl)nicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([NH:8][C:9](=[O:28])[N:10]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:27])[CH3:26])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH3:11])[CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].CC[N:45](C(C)C)C(C)C>CN(C=O)C>[CH3:26][N:25]([CH3:27])[C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([N:10]([CH3:11])[C:9](=[O:28])[NH:8][C:6]3[CH:7]=[C:2]([C:33]4[C:32]([C:31]([F:42])([F:41])[F:30])=[CH:40][CH:39]=[CH:38][C:34]=4[C:35]([NH2:45])=[O:36])[CH:3]=[CH:4][C:5]=3[CH3:29])[CH:17]=2)[CH:24]=[CH:23][CH:22]=1.[CH3:26][N:25]([CH3:27])[C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([N:10]([CH3:11])[C:9](=[O:28])[NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)[CH:3]=[CH:4][C:5]=3[CH3:29])[CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1NC(=O)N(C)c1cc(Nc2cccc(N(C)C)c2)ncn1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(N)=O)cccc2C(F)(F)F)cc1NC(=O)N(C)c1cc(Nc2cccc(N(C)C)c2)ncn1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Nc2cccc(N(C)C)c2)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(5-Amino-2-methyl-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea (0.26 mmol), 3-trifluoromethyl-benzoyl chloride (57 mg, 0.27 mmol) and DIEA (68 uL, 0.39 mmol) are dissolved in 10 mL anhydrous DMF. The reaction is stirred in the room temperature for 4 hours. After removing the solvent, the crude product is dissolved into DMSO and purified by reverse phase preparative HPLC to give the final product N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide as the white solid; 1H NMR (600 MHz, DMSO-d6) δ 12.67 (s, 1H), 10.44 (s, 1H), 9.84 (s, 1H), 8.56 (s, 1H), 8.40 (d, J=11.8 Hz, 2H), 8.28 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 3.35 (s, 3H), 2.92 (s, 6H), 2.35 (s, 3H); ESIMS m/z 565.3 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]=[C:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].C([O:14][C:15](O[Si](C)(C)C)=[CH:16][C:17]([O:21][Si](C)(C)C)=[CH:18][CH2:19][CH3:20])C.C(O)C.[F-].[NH4+]>O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[C:15]([OH:14])=[CH:16][C:17]([OH:21])=[C:18]([CH2:19][CH3:20])[C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)C=C=CC(=O)OC
Reactant: CCC=C(C=C(OCC)O[Si](C)(C)C)O[Si](C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1c(O)cc(O)c(C(=O)OC)c1CC(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
The above-obtained penta-2,3-dienedioic acid dimethyl ester (4.6 g, 30 mmol) and 1-ethoxy-1,3-bis(trimethylsiloxy)hexa-1,3-diene (13 g, 41 mmol) were mixed and stirred at a room temperature for 1.5 hours. The reaction mixture was added with ethanol (100 mL) and ammonium fluoride (5.4 g) and stirred at a room temperature for 2 hours. The reaction mixture was further added with water and extracted with ethyl acetate 3 times. The organic layers were combined, sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was triturated with hexane (50 mL) to obtain Compound 23 (3.2 g, 40%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:21][Si:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:12]1[CH:13]=[C:9]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:10]=[N:11]1
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)cn1
Temperature: 80 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a microwave at 80° C. for 30 min, then allowed to cool to rt and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile, as an oil, LC/MS (M+H)+: 300.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH2:27]O)[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C.CS([Cl:40])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:40][CH2:27][C:15]1[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of [4-(5-methyl-3-phenyl-isoxazol-4-yl)-1-(4-nitro-phenyl)-1H-imidazol-2-yl]-methanol (50 mg, 0.13 mmol) in DCM (5 mL) at 0° C. was added triethylamine (92.6 μL, 0.66 mmol) and methanesulfonyl chloride (30.97 μL, 0.40 mmol) and the resulting mixture allowed to warm up to room temperature over 3 h and then stirred for a subsequent 2 h. The mixture was then poured onto a saturated solution of sodium hydrogen carbonate and extracted with DCM. The combined organic layers were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (37 mg, 70%) which was obtained as a yellow foam. MS: m/e=395.0 [M+H]+.