Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=3[CH3:22])[N:13]=2)[CH:10]=1)=[O:4].[CH3:23][S:24]([CH2:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([O:21][CH2:29][CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:18][C:19]=3[CH3:20])[N:13]=2)[CH:10]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)nn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cc(OCCCS(C)(=O)=O)cc3C)nn2c1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2-(4-hydroxy-2,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (0.2 g, 0.673 mmol) in acetonitrile (5 mL) is added toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester (0.196 g, 0.673 mmol) and potassium carbonate (0.278 g, 2.019 mmol) at room temperature and the reaction mixture is heated at 100° C. for 16 hours. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a light yellow solid (198 mg, 70%). LCMS m/z 418 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol (208 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (273 mg, 91%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].B(F)(F)F.[CH3:24]COCC>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH3:24])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Yield: 73 %

Procedure:
A solution of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-acetic acid (138.5 g., 0.457 mole) in methanol (1.5 1.) and containing boron trifluoride etherate (325 g., 2.28 mole) is refluxed for 3/4 hour. The solvent is distilled at reduced pressure and the product which remains is filtered, washed with sodium bicarbonate and water and dried. The methyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate thus obtained (81 g., 73% yield) melts at 134°-137° C. after recrystallization from benzene.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:18][CH:17]([O:20][CH2:21][CH3:22])[O:16][CH2:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OC2CCCC2)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1ccc(OC2CCCC2)cc1)OCC
Temperature: 80 °C

Procedure:
A suspension of 4-cyclopentyloxyaniline (8.86 g), bromoacetaldehyde diethyl acetal (13 g), potassium carbonate (13.8 g) and dimethylformamide (100 ml) was heated at 80° C. for 6 hours. Cooling was followed by filtration and concentration of the filtrate. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1). The product with the molecular weight of 293.41 (C17H27NO3) was obtained in this way; MS (ESI): 294 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[NH2:8])(=[O:4])=[O:3].Cl.C1(C)C=CC=CC=1.[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:8]=[C:26]=[O:25])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:14])([F:15])[F:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(N=C=O)ccc1OC(F)(F)F
Reaction time: 8 h

Procedure:
To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500 mg) dissolved in ethyl acetate (6 mL) was added 3 N hydrochloric acid in ethyl acetate (5 mL) followed by concentration in vacuo. The residue was treated with toluene (3×5 mL) and each time concentrated in vacuo. To the residue was added toluene (10 mL) and diphosgene (6 mmol, 0.73 mL) under a nitrogen atmosphere and the suspension was gently refluxed for 2 hours. Additional diphosgene (6 mmol, 0.73 mL) was added and refluxing was continued overnight. The reaction mixture was concentrated in vacuo to afford 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)(Cl)(Cl)Cl>[CH:10]1[C:11]2[N:12]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(C)C(=O)Cl
Reactant: OCCOCCn1c2ccccc2c2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)OCCOCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
1.05 g (4.12 mmol) 4 and 0.65 g (6.22 mmol) methacryloyl chloride were dissolved in 15 ml of carbon tetrachloride. After the addition of 2.6 g activated molecular sieves (3 Å), the mixture was heated to reflux for 24 h. After cooling down to room temperature, it was filtered over basic alumina using 20% THF in CCl4. Evaporating the solvent yielded 0.8 g (60.1%) of a viscous yellow oil. Rf=0.44 (EtOAc/hexanes: 2/8). 1H NMR (CDCl3, 500 MHz, 20° C.): d 8.10 (t, 2H, J=7.76 Hz), 7.44 (m, 4H), 7.23 (m, 2H), 5.99 (s, 1H), 5.51 (s, 1H), 4.49 (t, 2H, 5.95 Hz), 4.19 (t, 2H, J=4.75 Hz), 3.88 (t, 2H, J=5.95 Hz), 3.59 (t, 2H, J=4.75 Hz), 1.88 (s, 3H). 13C NMR (CDCl3, 125 MHz, 20° C.): d 167.3, 140.6, 136.0, 125.8, 125.7, 122.9, 120.3, 119.0, 108.8, 69.5, 69.3, 63.7, 43.2, 18.2.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.C#N.[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29]Br)=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]>O.C(#N)C>[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29][C:1]#[N:2])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Reactant: [C-]#N
Agent: C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 60 °C

Procedure:
To a mixture of sodium cyanide (562 mg, 11.5 mmol) in water (3 mL) was carefully added mixture of sulfuric acid (2.9 mL, 5.5 mmol) at 0° C. (the reaction generates hydrogen cyanide and must be run in a fume hood with good ventilation), followed by a solution of 6-acetyl-3-(bromomethyl)-4-chloro-3′-fluorobiphenyl-2-carbonitrile (414 mg, 1.13 mmol) in acetonitrile (10 mL). The reaction was heated at 60° C. for 1 hour with pH adjusting to 9 by the addition of solid sodium cyanide. The reaction was cooled and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane (146 mg, 41%). LCMS calculated for C17H11ClFN2O (M+H)+: m/z=313.1; Found: 313.1.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:8]12[CH2:13][CH2:12][CH:11]([CH:10]=[CH:9]1)[CH:3]1[CH:2]2[C:1](=[O:7])[NH:5][C:4]1=[O:6])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1=CC=CCC1
Reactant: O=C1C=CC(=O)N1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
13.5 g (0.138 mol) of maleimide and 25.3 g (0.17 mol) of ethyl 1,3-cyclohexadiene-1-carboxylate are heated under reflux with 1.4 g of 4-(tert-butyl)pyrocatechol in 275 ml of toluene overnight. The mixture is concentrated and the residue is recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)[CH:27]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1cncc(C2CCCCN2)c1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2c2cccnc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-3-yl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.99 minutes; C27H25Cl2N5O2 (522.43); mass spectrum: (M−H)−=521/523/525 (chlorine isotope).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([NH:22][C:23]3[N:28]=[C:27]([N:29]([CH:39]4[CH2:41][CH2:40]4)CC4C=CC(OC)=CC=4)[C:26]4=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]4[N:24]=3)[C:15]=2[Cl:47])[CH2:10][CH:9]1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=O)(C)(C)C.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[Cl:47][C:15]1[C:16]([NH:22][C:23]2[N:28]=[C:27]([NH:29][CH:39]3[CH2:40][CH2:41]3)[C:26]3=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]3[N:24]=2)=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:48]([N:49]([CH3:51])[CH3:50])=[O:52])[CH2:10]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 135.1 %

Procedure:
Tert-butyl-4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (200 mg, 0.275 mmol) was taken up in DCM (2 mL) and cooled to 0° C. 2,6-Lutidine (0.096 mL, 0.826 mmol) was added, followed by drop wise addition of TMS-OTf (0.149 mL, 0.826 mmol). The reaction was stirred at 0° C. for 10 min, then brought to room temperature and stirred for 20 min. The reaction was quenched with 2M K3PO4 solution and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 188 mg of a yellow solid. The material was purified by flash column chromatography (0-70% 10% MeOH/DCM; 24 g column). 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (133 mg) was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][S:18][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1)[CH3:24]
Reactant: CCOC(=O)CS
Reactant: Clc1ccc(CNc2nc(Cl)cc(Cl)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1cc(Cl)nc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 3.25 g. of 4,6-dichloro-2-(p-chlorobenzylamino)pyrimidine, 1.35 g. of ethyl mercaptoacetate and 0.95 g. of sodium bicarbonate in 50 ml. of ethanol was heated under reflux overnight. The reaction mixture was filtered. A crystalline material was deposited which amounted to 2.7 g., m.p. 122°-125°C. The analytical sample was obtained by recrystallization from ethanol, m.p. 122°-125°C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39](OC2C=CC([N+]([O-])=O)=CC=2)=[O:40])=[CH:13][CH:12]=1)#[N:10].O>O1CCCC1>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[O:40])=[CH:15][CH:16]=1)#[N:10]
Reactant: CC(C)(C)CO
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) in dry tetrahydrofuran (1 mL) is cooled at −78° C. and treated with sodium hydride (60% in mineral oil, 5 mg, 0.11 mmol). After 20 min, a solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 60 mg, 0.10 mmol) in tetrahydrofuran (1 mL) is added and the mixture is stirred for 5 h at room temperature. Another portion of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) is added and the mixture is stirred over night. Another portion of 2,2-dimethyl-1-propanol (18 mg, 0.20 mmol) is added and the mixture is heated at 50° C. for 2 h. Water is added and the mixture is extracted with dichlormethane. The organic layer is concentrated under reduced it) pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane to cyclohexane/ethyl acetate 1:1). Yield: 12 mg; ESI mass spectrum [M+H]+=526; Retention time HPLC: 0.76 min (X012_S01).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28](N(OC)C)=[O:29]>O1CCCC1>[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28]([C:22]1[S:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:29]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccs2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.9 ml, 2.25 mmol) was added dropwise to a solution of tert-butyl-4-(thiazol-2-yl)-1,4-diazepane-1-carboxylate (570 mg, 2 mmol) in tetrahydrofuran (7 ml), cooled to −78° C. Thirty minutes later, a solution of 2-fluoro-N-methoxy-N-methylnicotinamide (370 mg, 2 mmol) in tetrahydrofuran (2 ml) added dropwise. The reaction mixture was stirred at −78° C. for one hour, then at 0° C. for an extra hour. It was quenched with a saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with ethyl acetate, then washed with brine. The organic was dried over magnesium sulfate, then concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate) to afford the title compound (300 mg, 38%). 1H NMR (CD3OD): 1.42 (9H, s), 1.90-2.00 (2H, MO, 3.45-3.50 (2H, m)<3.65-6.75 (2H, m), 3.80-3.90 (2H, m), 7.46-7.49 (1H, t), 7.67-7.69 (1H, d), 8.10-8.15 (1H, t), 8.39-8.40 (1H, d). MS (ES+): 407.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1
Reactant: O=C(Nc1cnc2[nH]cc(Br)c2c1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Benzyl 3-bromo-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (10.22 g, 29.53 mmol) in dry THF (120 mL) was cooled to 0° C. and treated portionwise with sodium hydride (1.193 g, 29.83 mmol, 1.01 Eq). The mixture was allowed to stir at this temperature for 1 hour and then treated with tosyl chloride (5.744 g, 30.13 mmol, 1.02 Eq) in THF (15 mL) over a period of 10 minutes. The mixture was left to stir at room temperature for a further 4 hours and then quenched with sat. aq. ammonium chloride. The mixture was diluted with EtOAc and the organic layer separated, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by column chromatography (5% MeOH/DCM) to give 11.09 g (75%) of brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[S:8][C:7]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[N:6][C:5]1=[O:20])[CH3:3].C1C(=O)N(Br)[C:23](=[O:24])C1>C(Cl)(Cl)(Cl)Cl>[CH:2]([C:4]1([O:24][CH3:23])[S:8][C:7]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:13][CH:12]([CH2:18][CH:16]([CH2:15]4)[CH2:17]2)[CH2:11]3)=[N:6][C:5]1=[O:20])([CH3:1])[CH3:3]
Reactant: CC(C)C1SC(NC23CC4CC(CC(C4)C2)C3)=NC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC1(C(C)C)SC(NC23CC4CC(CC(C4)C2)C3)=NC1=O
Temperature: 0 °C

Procedure:
A mixture of 5-(1-methylethyl)-2-(tricyclo[3.3.1.13,7]dec-1-ylamino)-1,3-thiazol-4(5H)-one (146 mg, 0.5 mmol) and NBS (107 mg, 0.6 mmol) in CCl4 (60 mL) was stirred at reflux for 30 min. The resulting mixture was cooled to 0° C., and filtered to remove the solid. The residue was then concentrated in vacuo and diluted with CH2Cl2 (20 mL). To this mixture was added MeOH (200 uL) and DIEA (200 uL). The mixture was stirred for 30 min, then was concentrated in vacuo and purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as white solid. MS (ES+): 323 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[C:22]([N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:37][CH:34]2[CH2:33][CH2:32][N:31]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:24][N:23]=3)[CH2:36][CH2:35]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 78.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (200 mg, 0.667 mmol) was dissolved in dry DMF (2 mL) under nitrogen atmosphere. 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (188 mg, 0.674 mmol) was added followed by TEA (68 mg, 0.667 mmol) and the reaction mixture was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (284 mg, 77.6%). 1H NMR (500 MHz, CDCl3): δ 1.46-1.54 (m, 2H), 1.73-1.79 (m, 1H), 2.51 (t, 2H), 3.12-3.19 (m, 1H), 3.79-3.82 (m, 2H), 5.28 (d, 1H), 7.44-7.46 (m, 3H), 7.53-7.55 (m, 2H), 7.72 (s, 1H), 8.33 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 27.82, 32.36, 47.43, 50.27, 61.80, 107.32, 120.35 (q, J=33.4 Hz), 121.28, 123.48 (q, J=271.3 Hz), 125.36, 128.94, 130.17, 131.85, 134.16, 136.15, 143.10, 159.87, 160.06; Mass Spectrum: M+H+ 543.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23](Cl)=[O:24])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.O>C1COCC1>[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:24])[CH2:11][CH:12]3[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]3)[CH2:19]1)[CH2:17]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 82.8 %

Procedure:
In a manner analogous to Example 3(b), 0.95 g (10 mmoles) of phenol in 10 ml of THF are treated with 332 mg 11 moles) of sodium hydride (80% in oil). There is then slowly introduced a solution of 3.2 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF. The reaction is permitted to proceed at ambient temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl ether, washed with water, dried on magnesium sulfate and evaporated. The residue is chromatographed on silica, eluting with a 60:40 mixture of hexane and dichloromethane. After evaporation and precipitation in hexane, 3 g (83% yield) of the expected ester having a melting point of 165°-166° C. are isolated.