Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1(C)[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=C[CH:28]=1>C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][S:22]([C:17]2[CH:16]=[CH:21][C:20]([CH3:28])=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
A solution of N-Boc-4-piperidinemethanol, 5.0 g (23.2 mmol) in chloroform, 50 mL, was prepared. Toluene sulfonyl chloride, 5.75 g (30.2 mmol), in 5.6 mL of pyridine (69.6 mmol) was added. The solution was stirred under nitrogen allowed to stir for 24 hours. Standard workup and chromatographic purification provided the title compound. Yield 6.0 g
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([N:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:5]2[N:28]=[CH:29][CH:30]=[C:4]2[N:3]=1.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[C:14]([O:13][C:12]([N:11]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)[C:6]1[N:5]2[N:28]=[CH:29][CH:30]=[C:4]2[N:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([OH:32])=[O:10])=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC=O)c(Cl)nc3ccnn23)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(=O)O)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
To a mixed solution of water (0.5 mL) and tert-butanol (5 mL) containing tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (431 mg, 1.0 mmol), sodium dihydrogen phosphate (1.56 g, 10 mmol), 2-methyl-2-butene (1.1 mL, 10 mmol) and sodium chlorite (181 mg, 2.0 mmol) were added, and this mixture was stirred at room temperature for 4 hr. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (468 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(Cl)Cl>C(N(CC)CC)C.[Pd](Cl)Cl.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>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCNc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 50 °C

Procedure:
A solution of 1.608 g (6.7 mmol) of 4,4-dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline in 1.5 ml of triethylamine in a heavy-walled tube was degassed under argon and then treated with 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was degassed again under argon, treated with 2.09 g (21.2 mmol) of trimethylsilylacetylene and the tube was sealed. The mixture was heated at 50° C. for 48 hours. After cooling to room temperature methylene chloride was added to the reaction mixture and the mixture filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([C:63](=[O:71])[NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:60]2[N:72]([C:75](=[O:84])[CH:76]([NH2:83])[CH:77]3[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]3)[CH2:73][CH2:74][CH:59]12)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN1C(=O)CCC1.CCOCC>[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([C:63](=[O:71])[NH:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:60]2[N:72]([C:75](=[O:84])[CH:76]([NH:83][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:77]3[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]3)[CH2:73][CH2:74][CH:59]12)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of Boc-N(Me)Ala-OH (155 mg, 0.76 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (290 mg, 0.76 mmol) and DIPEA (0.15 mL, 0.87 mmol) followed in 15 min by the addition of 40 (366 mg, 0.73 mmol). The reaction mixture was allowed to warm to ambient temperature. After 18 h, the solution was diluted with Et2O, washed with H2O, 1M HCl, H2O, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 41 (443 mg) as a white foam that was used without further purification. Mass spectrum, m/z [690.8] (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[C:25]1([S:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][N:34]([S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])[CH2:35][CH2:36]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)n2n1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1-(phenylsulfonyl)piperazine (170 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (103.0 mg, 77%). 1H NMR (DMSO-d6) δ: 10.88 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.81-7.85 (m, 2H), 7.75-7.80 (m, 1H), 7.68-7.74 (m, 2H), 7.59 (d, 2H), 7.30 (s, 1H), 6.16 (s, 1H), 3.76-3.81 (m, 4H), 3.09-3.18 (m, 4H), 2.34 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 535.0 (M+H)+.
Reaction SMILES: CO[C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].FC(F)(F)C1C=C(C=CC=1OC)[C:21](O)=[O:22]>>[CH3:21][O:22][C:8]1[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1c(C(=O)O)cccc1C(F)(F)F
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1C(=O)O

Procedure:
In a similar manner are prepared 2-methoxy-3-trifluoromethylbenzoic acid and 3-trifluoromethyl-4-methoxybenzoic acid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:7][C:5]=1[NH2:6].[C:16]12(C(O)=O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.[CH4:29]>CO>[OH2:14].[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH:23]1[C:29]1[NH:6][C:5]3[CH:7]=[C:8]([S:12](=[O:14])(=[O:15])[NH2:13])[C:9]([Cl:11])=[CH:10][C:4]=3[N:3]=1)[CH2:25]2.[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH:23]1[C:29]1[NH:6][C:5]3[CH:7]=[C:8]([S:12](=[O:14])(=[O:15])[NH2:13])[C:9]([Cl:11])=[CH:10][C:4]=3[N:3]=1)[CH2:25]2
Reactant: C
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CO
Product: NS(=O)(=O)c1cc2[nH]c(C3C4CC5CC(C4)CC3C5)nc2cc1Cl
Product: O
Reaction time: 0.08 h

Procedure:
A mixture of 2.95 g of 2-amino-4-chloro-5-sulfamylaniline dihydrochloride and 2.70 g of 1-adamantanecarboxylic acid was ground together and heated at 190°-200° for 5 hours. The dark solid was dissolved in 500 ml of methanol, the methanol brought to a boil, charcoal added, boiling continued for five minutes, and the suspension then filtered through two sheets of filter paper, and then through Celite. Concentration in vacuo provided a solid which was then added to 100 ml of concentrated ammonium hydrozide and stirred for twenty minutes. The crude product was collected by filtration and recrystallized from acetonitrile to provide 0.5 g of colorless crystals, m.p. 207°-210°.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[N+:7]([C:10]1[CH:28]=[CH:27][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:26][C@H:24]([OH:25])[CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCl>[OH:25][C@H:24]1[CH2:26][N:18]([C:16]([O:15][CH2:14][C:13]2[CH:27]=[CH:28][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)=[O:17])[C@H:19]([C:20]([O:22][CH3:1])=[O:21])[CH2:23]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methanol (94.5 ml) and dichloromethane (945 ml) under ice cooling are dropwise added thionyl chloride (18.7 ml) and after 5 minutes stirring N-p-nitrobenzyloxycarbonyl-L-hydroxyproline (1: 72.4 g), and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuum to give crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.5 g) as pale yellow oil. This product can be used in the next step without further purification. IR ν (CHCl3) cm-1 : 3450, 1742, 1703, 1605. 1HNMR δ (CDCl3) ppm: 1.77(1H, s), 2.05 to 2.45(2H, m), 3.55 to 3.8(2H, m), 3.66, 3.76(3H, 2s), 4.49 to 4.62(2H, m), 5.06 to 5.35(2H, m), 7.43 to 7.56(2H, m), 8.22(2H, d, J=8.2 Hz).
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].CS([C:20]1[NH:21][CH:22]=[C:23]([CH3:28])[C:24]=1[N+:25]([O-:27])=[O:26])=O>>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:20]2[NH:21][CH:22]=[C:23]([CH3:28])[C:24]=2[N+:25]([O-:27])=[O:26])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: Cc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Agent: Cl
Product: Cc1c[nH]c(NCCSCc2csc(NC(=N)N)n2)c1[N+](=O)[O-]

Procedure:
The title compound is prepared from 2-(2-Guanidino-4-thiazolylmethylthio)-ethylamine dihydrochloride and 2-methylsulphinyl-4-methyl-3-nitropyrrole by a process analogous to that described in Example 1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 3-(3-(trifluoromethyl)phenylamino)benzoate (0.334 g; 1.08 mmol) in dioxane (14 mL) was added a solution of sodium hydroxide (0.130 g; 3.24 mmol) in water (3.24 ml). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to remove the dioxane. The aqueous solution was acidified with 6N hydrochloric acid, extracted with ethyl acetate (2×100 mL), dried and concentrated under reduced pressure to provide 0.303 g (99%) of 3-(3-(trifluoromethyl)phenylamino)benzoic acid which was directly used in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N[C@@H](C1C=NC(C)=CC=1)CCO.C1(C)C=CC=CC=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: Cc1ccc([C@H](N)CCO)cn1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc2cccnc2c1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Methyl quinoline-7-carboxylate (5 g, 0.01 mol) was dissolved in tetrahydrofuran (40 mL) at −20° C. under an atmosphere of nitrogen. 60% REDAL (60:40, Red-Al(R):toluene, 6.53 mL, 0.0201 mol) was added and allowed to stir at −20° C. for 4 hours. After warming to room temperature, the reaction was quenched slowly with water, concentrated under reduced pressure, partitioned between EtOAc and water, and filtered through Celite. The aqueous phase was extracted with EtOAc. The combined organic layers were dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[OH-].[K+].O.O.Br[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16]>CS(C)=O>[Br:16][C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
Into a 250 mL round-bottom flask were placed 18.72 g (0.17 mol) of 1,3-dihydroxybenzene (resorcinol) and 75 mL of DMSO. The solution was purged with nitrogen gas for one hour followed by adding 223.62 mL of 1.52M (0.34 mol) KOH-water water solution dropwise to the solution, with the reaction flask resting in an ice-bath. The reaction mixture was then heated at 100° C. for one day followed by distilling off most of the water from the reaction solution. The rest of reaction solvents were evaporated slowly under vacuum. The salt was dried at 120° C. under the vacuum line for at least two days. Then 75 mL of dry DMSO and 109.2 g (0.42 mol) of 1,2-dibromo tetrafluoroethane was transferred to the flask via a closed system. The mixture was stirred at 35° C. for 3 days. The reaction mixture was filtered to remove the KBr, then the reaction mixture was washed with acetone in a 500 mL separatory funnel and the organic layer was diluted with 150 mL of methylene chloride. The combined organic layer was washed first with 10% of sodium bicarbonate water solution, and then with 0.01N HCl and finally with distilled water until neutral. The solution was dried over sodium sulfate overnight. After the removal of the sodium sulfate by filtration and the evaporation of the solvents, the crude product was purified by distillation under reduced pressure with an oil bath at a temperature of 100-110° C. A total of 64 g (0.136 mol) of 1,3-di(2-bromotetrafluoro ethoxy)benzene was obtained in 80.4% yield, which had a boiling point of 76-80° C. (at 10−2 torr). The amount of hydrogen by-product in the product was about 5.4%.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C1N=CN([C:18]([N:20]2[CH:24]=N[CH:22]=[CH:21]2)=[O:19])C=1.CCN(C(C)C)C(C)C.[Br:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:48]=1[C:42]1(CCNC[CH2:43]1)[CH2:41][CH:40]2[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:48]=1[C:42]1([CH2:22][CH2:21][N:20]([C:18](=[O:19])[NH:1][CH:2]3[CH:9]4[CH2:10][C:5]5([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]3[CH2:4]5)[CH2:8]4)[CH2:24][CH2:43]1)[CH2:41][CH:40]2[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC3CC(O)(C5)C4)CC2)c2c(Br)cccc21
Reaction time: 1 h

Procedure:
A solution of 4-aminoadamantan-1-ol (628 mg, 3.76 mmol) in dry CH2Cl2 (2 mL) was added CDI (736 mg, 4.52 mmol) and DIEA (3.24 g, 25.12 mmol) at 0° C. under N2 and the mixture was stirred for 1 h. Ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (1.10 g, 3.14 mmol) was added and the mixture was stirred overnight. The mixture was washed with 5% aq HCl, and the organic layer was concentrated to give the crude product. Purification by preparative TLC followed by preparative HPLC gave two isomers of ethyl 2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C@@H:34]([NH2:38])[CH2:35][O:36]C)[NH:31][C:30]=2[CH:39]=1.[CH:40](N(C(C)C)CC)(C)C.O>O1CCOCC1.ClCCl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C@@H:34]([NH:38][C:2]3[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][N:11]([C:14]5[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=5)[CH2:10][CH2:9]4)[N:7]=3)[C@H:35]([OH:36])[CH3:40])[NH:31][C:30]=2[CH:39]=1
Reactant: COC[C@H](N)c1nc2ccc(Cl)cc2[nH]1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O)[C@H](Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)c1nc2ccc(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
200 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 353.41 mg (R)-1-(6-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine and 179.62 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 2×0.3 hours. Then the reaction mixture is combined with water and dichloromethane and extracted. The product is purified by semipreparative HPLC (method A). 150 mg of the product are obtained as a powder. Analytical HPLC-MS (method B): RT=1.90 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]([NH:32][OH:33])=[NH:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34].N1C=CC=CC=1.Cl[C:42](OCC(CC)CCCC)=[O:43]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:31][C:42](=[O:43])[O:33][N:32]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1-c1nc(NCCc2noc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Under Ar, to a soln of the product of Example 242, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100 mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added 2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was diluted with xylene (10 mL) and heated to reflux for 18 h to give the crude material, which was purified by preparative hplc to give the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [N:1]1([C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C=C(c1ccc(CC)cc1)n1cnc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccc(CC)cc1)n1cnc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (E/Z mixture, 181 mg, 566 μmol) in a mixture of ethanol and water (10:1, 2.75 mL) was added palladium on carbon (27 mg, 10% w/w Pd) and ammonium formate (143 mg, 2.26 mmol). The suspension was brought to reflux for 3 hours, cooled to room temperature, and was filtered through a pad of Celite® and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4) to afford the title compound, 1H NMR: (CDCl3), 8.03 (s, 1H), (d, J=6.96, 1H), 7.31-7.06 (m, 7H), 6.01 (dd, J=8.79, 6.59, 1H), 4.04 (t, J=6.96, 2H), 3.38 (dd, J=15.75, 8.79, 1H), 3.31 (dd, J=15.75, 6.59, 1H), 2.62 (q, J=7.69, 2H), 1.18 (t, J=7.69, 3H), 1.09 (t, J=6.96, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:15]2[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:17](=[O:34])[NH:16]2)=[C:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:35][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.C(O)(=O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:15]2[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[C:17](=[O:34])[N:16]2[CH3:35])=[C:7]([S:9]([N:12]([CH3:13])[CH3:14])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}-N,N-dimethylbenzene sulfonamide (50 mg, 108 μmol) was initially charged in absolute THF (4.5 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (130 μl, 130 μmol; 1.2 eq.) was added at −78° C. After 30 min of stirring, iodomethane (77 mg, 542 μmol; 5 eq.) in THF (1 ml) was added, and the mixture was stirred for 16 h with gradual warming from −78° C. to RT. A little acetic acid was then added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (7.6 mg, 14% of theory).