Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([F:42])[CH:34]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[C:35]([F:42])[CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(Cl)cc1F
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 4-chloro-2-fluorophenylboronic acid (0.065 g; 0.375 mmol) in a mixture of DME-water (3:1, 1 mL) was heated at 100° C. for 2.5 h. The mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.049 g (38%) of the title compound as a colorless oil.
Reaction SMILES: C1(O)CCCCC1.[CH2:8]([C@@H:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:11]1=[O:18])[CH3:9]>>[CH2:8]([C@@H:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C@H:11]1[OH:18])[CH3:9]
Reactant: CC[C@@H]1CC(C)(C)CCC1=O
Solvent: OC1CCCCC1
Product: CC[C@@H]1CC(C)(C)CC[C@H]1O

Procedure:
By proceeding as described above for the oxidation of its enantiomer, the above cyclohexanol (1.56 g, 10.0 mmol) was oxidized to (-)-(2R)-2-ethyl-4,4-dimethyl-1-cyclohexanone (1.36 g, 88%, 97% e.e. determined under the conditions described above).
Reaction SMILES: [H-].[Na+].C([N:21]([C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH:42]=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])CCCCCCCCCCCCCCCCC.[CH3:48][S:49]([C:52]1[CH:66]=[CH:65][C:55]([CH2:56]P(=O)(OCC)OCC)=[CH:54][CH:53]=1)(=[O:51])=[O:50]>COCCOC>[CH2:22]([N:21]([CH2:40][CH2:47][CH2:46][CH2:45][CH2:44][CH2:41][CH2:42][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[C:46]1[CH:47]=[CH:40][C:41]([CH:42]=[CH:56][C:55]2[CH:54]=[CH:53][C:52]([S:49]([CH3:48])(=[O:50])=[O:51])=[CH:66][CH:65]=2)=[CH:44][CH:45]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1C=O
Reactant: CCOP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Yield: 101.5 %

Procedure:
To a solution of 420 mG of 60% sodium hydride dispersion (0.011 mol), 6.26 g (0.01 mol) of N,N-dioctadecylaminobenzaldehyde and 40 mL of dry, freshly distilled 1,2-dimethoxyethane (DME) under nitrogen, at room temperature, with vigorous stirring, was added a solution of 3.06 g (0.01 mol) of diethyl 4-methylsulfonylbenzylphosphonate in 10 mL 1,2-dimethoxyethane. The mixture immediately turned bright yellow. The reaction mixture was heated at reflux for 2 hours. After cooling, the bright yellow solution was poured over 100 g of crushed ice under a nitrogen blanket. The bright yellow solid was collected by filtration, washed with cold water, and air dried. Recrystallization from ethanol yielded 3.95 g (50.7%) of bright yellow powder mp 75°-76° C.
Reaction SMILES: [C:1](=[S:11])([S:3][CH2:4][CH2:5][C:6]([F:10])=[C:7]([F:9])[F:8])[NH2:2].Cl.Cl[CH2:14][CH:15]=O>O1CCOCC1>[F:10][C:6](=[C:7]([F:9])[F:8])[CH2:5][CH2:4][S:3][C:1]1[S:11][CH:14]=[CH:15][N:2]=1
Reactant: O=CCCl
Reactant: NC(=S)SCCC(F)=C(F)F
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)=C(F)CCSc1nccs1
Reaction time: 4 h

Procedure:
15.1 g (64.8 mmol; purity 86.3%) of 3,4,4-trifluoro-3-butenyl dithiocarbamate in 100 ml of dioxane are admixed with 0.2 ml of conc. hydrochloric acid and 12.4 g (71.2 mmol) of 45% aqueous chloroacetaldehyde solution. The mixture is boiled for 4 h under argon, and another 1 ml of chloroacetaldehyde solution is added after 2 h. The mixture is then concentrated by evaporation under reduced pressure, the residue taken up in dichloromethane and washed with water, and the organic phase concentrated by evaporation under reduced pressure after drying over MgSO4. 16 g (94.4% of theory; purity by GC/MS: 86.1 area %) of an oil are obtained, which may be distilled at 0.4 T/86° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([OH:24])[CH:23]=2)[O:20][C:19]([CH3:26])([CH3:25])[CH2:18][C:17]3([CH3:28])[CH3:27])=[CH:8][CH:7]=1)[CH3:5].[OH-].[K+]>CO.O1CCCC1>[OH:24][C:22]1[CH:23]=[C:14]([C:13]#[C:12][C:9]2[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[C:3]([OH:29])=[O:2])=[CH:7][CH:8]=2)[CH:15]=[C:16]2[C:21]=1[O:20][C:19]([CH3:26])([CH3:25])[CH2:18][C:17]2([CH3:27])[CH3:28]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-propionic acid methyl ester (Intermediate 22, 0.018 g, 0.046 mmol) in methanol (1 mL) and tetrahydrofuran (0.5 mL) was treated with a 2M solution of potassium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.017 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25](Cl)=[O:26])[CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:25](=[O:26])[CH2:24][C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[C:21]([CH3:23])[CH:20]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: Cc1cc(C)cc(CC(=O)Cl)c1
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (989 mg in 15 mL of dry 1,2-dichloroethane) was added a solution of (3,5-dimethylphenyl)acetyl chloride (860 mg in 5 mL dry 1,2-dichloroethane) and the mixture heated at reflux on an oil bath. After 18 hours, an additional portion of (3,5-dimethylphenyl)acetyl chloride (274 mg in 1.5 mL dry 1,2-dichloroethane) was added and the mixture heated at reflux for an additional 5 hours. At this time the reaction was cooled and the solvent removed in vacuo. Recrystallization of the crude product from methanol gave the title compound (1.17 g).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][CH2:23][C:24]([OH:26])=O)[C:15]1=[O:27].[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>O1CCCC1>[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH:32][C:24](=[O:26])[CH2:23][CH2:22][N:16]1[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH3:13])[C:15]1=[O:27]
Reactant: CN1C(=O)N(CCC(=O)O)C(C)(C)C1=O
Reactant: COC(CN)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CNC(=O)CCN1C(=O)N(C)C(=O)C1(C)C)OC

Procedure:
82.7 g (0.51 mol) of 1,1'-carbonyldiimidazole in 5.0 l of tetrahydrofuran are allowed to react as described in Example 1, with 93.08 g (0.5 mol) of 3-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)propionic acid and are subsequently reacted with 53.62 g (0.51 mol) of 2-aminoacetaldehyde dimethyl acetal. The reaction mixture is evaporated in a rotary evaporator, and the imidazole present in the residue is removed by distillation at a bath temperature of 120° C./0.1 mmHg for 3 hours, giving 134.1 g (98.1% of theory) of a brownish, liquid crude product, which is recrystallized from 130 ml of ethyl acetate, giving 88.1 g (65.0% of theory) of colourless, crystalline N-(2,2-di methoxyethyl)-3-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)propionamide, whose melting point is 86.4° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 20 g (87 mmol) of (±)-4-bromo-α-hydroxyphenylacetic acid, 200 ml of methanol and 2 ml of concentrated sulfuric acid was stirred for 3 hours at room temperature. To the mixture 50 ml of water was added. After the solution was extracted with ethyl acetate, the organic extract was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and it was dried on anhydrous magnesium sulfate. After removing the solvent, the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1)), and 19.5 g of (±)-methyl 4-bromo-α-hydroxyphenylacetate was obtained (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
(S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (17.0 g) was dissolved in methanol (200 ml) and cooled to 0° C. After 2N NaOH (46.8 ml) was added, the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure to remove methanol. The concentrate was poured to 6N HCl while cooling with ice. The precipitated crystal was filtered and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide (1.10 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17]C1C=CC(N)=CC=1>>[F:17][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Reactant: Nc1ccc(F)cc1
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O

Procedure:
The title compound was prepared following the procedure described in Step 1 for the synthesis of 2a using 4-fluoroaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.15 (3H, t, J=7.080 Hz), 4.1 (2H, q, J=7.08 Hz), 7.61 (1H, dd, J=8.30, 2.93 Hz), 7.68 (1H, dd, J=9.03, 4.63 Hz), 7.80 (1H, dd, J=9.27, 2.93 Hz), 8.56 (1H, s). m/z 236.5 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C.CS(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 6-nitro-7-bromo-1,4-dihydro-2,3-quinoxalinedione (87 mg, 0.30 mMol) in ethanol (3 mL) and DMSO (0.5 mL) was added SnCl2.2H2O (343 mg, 1.50 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution which was refluxed for another 1 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 50 mg (67%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 21 mg of pure as bright yellow needles, mp: >300° C. (dec. from 315° C.), changed color from 300° C. NMR (1H, DMSO-d6): d 5.257 (s, 2H); 6.558 (s, 1H); 7.087 (s, 11t); 11.599 (s, 1H); 11.792 (s, 1H). HRMS: calcd for C8H6N3O2Br (M+) m/z: 254.9642; found 254.9630. Potency relative to DCK: 7.1%.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3]([S:9](=[O:11])(=[O:10])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:2][CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(Cl)ccc21
Yield: 14 %

Procedure:
In the similar fashion using route 16 general procedure 61, using 2-amino-4-chloro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 292) (150 mg, 0.45 mmol), t-butyl nitrite (0.08 ml, 0.67 mmol), AcOH (1.5 ml) and THF (1.5 ml) gave the title compound (20 mg, 14%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=O)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[S:31])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=S)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 153.7 %

Procedure:
4-chloro-N-p-tolyl-3-trifluoromethyl-benzamide (1.0 g, 3.19 mmol), Lawesson's reagent (774 mg, 0.6 eq.) and toluene (2.5 mL) is mixed in a microwave vial. The mixture is heated to 120° C. for 1000 seconds using microwave irradiation. The mixture turned into clear solution. Ether (50 ml) is added to dilute the reaction mixture. The solution is then washed with brine, dried over MgSO4, filtered and concentrated. The mixture is purified by column chromatography (EtOAc/Hexanes=5/95) to afford 970 mg (92%) of 4-chloro-N-p-tolyl-3-trifluoromethyl-thiobenzamide as a yellow solid.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H: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])=[N:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([B:27]([OH:29])[OH:28])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:5]1[NH:6][C:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([B:27]([OH:29])[OH:28])=[CH:25][CH:26]=2)=[CH:3][N:4]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Reactant: C#Cc1ccc(B(O)O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#Cc2ccc(B(O)O)cc2)[nH]1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
Nitrogen was bubbled through a solution of (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.41 mmol), 4-ethynylphenylboronic acid (90 mg, 0.62 mmol) and copper(I) iodide (15.7 mg, 0.083 mmol) in DMF (5 mL) and triethylamine (0.30 mL, 2.0 mmol) for 15 min. Then Pd(PPh3)4 (23.86 mg, 0.021 mmol) was added and the reaction mixture was vacuum flushed with nitrogen (4×,), sealed and heated at 60° C. ON. The crude reaction was concentrated to dryness, dissolved into DMF/MeOH and purified by Prep HPLC (MeOH/water with ammonium acetate buffer) to yield (S)-4-((2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)ethynyl)phenylboronic acid (113.8 mg, 0.299 mmol) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=2)[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1c(-c2ccccc2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 80 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (2.5 g, 9.5 mmol), tetraphenylltin (6.1 g, 14.3 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuo, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 1.0 g (3.8 mmol, 41%) of 2,4-dinitro-6-phenylaniline, which was converted to the diamine (0.72 g, >95%) on hydrogenation (H2/Pd—C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C(C)C)=[C:19]([I:27])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:27])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of the product of Step B (0.2 g, 0.4 mmol) in anhydrous CH2Cl2 (2 ml) 1 M BCl3 in CH2Cl2 (3 ml) was added drop wise at rt. After 1 h, more of 1M BCl3 in CH2Cl2 (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with CH2Cl2 (20 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrates was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.145 g, 79%), as colourless solid. 1H-NMR (CDCl3) 8.47 (d, 1H, J=1.95 Hz); 8.21 (d, 1H, J=2.1 Hz); 8.06-8.04 (m, 1H); 8.03-8.02 (m, 1H); 7.07 (d, 1H, J=8.49 Hz); 7.00 (d, 1H, J=8.7 Hz); 4.08 (t, 2H, J=6.45 Hz); 1.94-1.87 (m, 2H); 1.09 (t, 3H, J=7.44 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([C:30]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:31])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Agent: NC(CO)(CO)CO
Solvent: CC(Cl)Cl
Product: O=C1c2ccccc2OC2(CCN(C(=O)C3CCCC3)CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.010 mmol) in dichloroethane (0.7 mL) were added cyclopentanecarbonylchloride (0.020 mmol) and poly(4-vinylpyridine) (2% cross-linked, Aldrich, CAS#9017-40-7) (5.3 mg). The mixture was stirred overnight at 25° C. To the reaction mixture was added PS-trisamine (Argonaut, product number 800229, loading; 4.36 mmol/g) (6.9 mg), and the mixture was stirred overnight at 25° C. The mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:42][O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=O)[O:55]C2C=CC([N+]([O-])=O)=CC=2)=[CH:49][CH:48]=1.CCN(CC)CC>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:54]([NH:53][C:50]5[CH:49]=[CH:48][C:47]([O:46][CH2:45][CH2:44][O:43][CH3:42])=[CH:52][CH:51]=5)=[O:55])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
A mixture of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 4, step 2, 0.158 g, 0.277 mmol) and 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.118 g, 0.354 mmol) in DCM (3 mL) was stirred at rt for 3 days. Et3N (0.20 mL) was added followed by 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.142 g, 0.428 mmol). The reaction mixture was stirred at rt for 2 h. The yellow solid was collected and washed with DCM to give 0.176 g of crude 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea, which was taken into the next step without further purification.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Li+].C[CH:13]([N-:15]C(C)C)C.C(P(=O)(OCC)OCC)#N>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([C:13]#[N:15])=[CH:2]1
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CCc2ccccc21
Temperature: -10 °C
Yield: 829.2 %

Procedure:
A solution of 1-indanone (100 g, 0.756 mole) in 1 L of dry THF was cooled to −10° C. followed by the addition of 38.7 ml of 2M LDA (75.6 mmole). After 20 min of stirring at −10° C. diethyl cyanophosphonate (126.28 ml, 0.8323 moles) was added over 1 hour. The reaction was warmed to room temperature until no indanone was visible by TLC. The reaction was again cooled to −10° C. and borotrifluoride diethyl etherate (191 ml, 1.513 moles) was added dropwise. After warming to room temperature THF was evaporated and the resulting dark oil dissolved in EtOAc, washed with water and dried over MgSO4. Evaporation of the EtOAc and distillation of the resulting oil afforded 88.4908 g of 1H-indene-3-carbonitrile (83% yield).