Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[C:7]([OH:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)[OH:11].[F:16][C:17]([F:35])([F:34])[C:18]1[CH:19]=[C:20]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=1.B(F)(F)F.CCOCC>O>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:19]=[C:20]([CH:24]([C:12]2[C:10](=[O:11])[C:9]([CH3:13])=[C:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH3:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C(O)CCCCCC(O)c1cccc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: ClCCCl
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2cccc(C(F)(F)F)c2)=C(C)C1=O
Temperature: 80 °C
Yield: 23.7 %

Procedure:
1,2-Dichloroethane (15 ml) was added to 0.76 g (5.0 mmole) of trimethylhydroquinone and 1.45 g (5.0 mmole) of 7-(3-trifluoromethylphenyl)-7-hydroxyheptanoic acid, and the mixture was warmed to 80° C. under stirring and admixed with 0.19 ml (5.0×0.3 mmole) of boron trifluoride ethyl etherate, followed by stirring at 80° C. for 2 hours. After the reaction solution was cooled by standing at room temperature, the solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). A solution of 2.7 g (10.0 mmole) of ferric chloride in water (10 ml) was added to the solution, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and ethyl acetate was added to the residue to carry out extraction. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated, and the residue was chromatographed on a silica gel column chromatography, followed by elution with isopropyl ether. The fractions containing the object compound were collected and concentrated under reduced pressure, and the residue was recrystallized from isopropyl ether-hexane to give 0.50 g (24%) of 7-(3-trifluoromethylphenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)heptanoic acid.
Reaction SMILES: [CH:1]([C:3]1[C:16]2[C:17]3=[C:18]4[C:13](=[CH:14][CH:15]=2)C=CC=[C:9]4[CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1)=[CH2:2].C([Li])CCC.CC[O:26][CH2:27][CH3:28]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:28]1([CH:27]=[O:26])[C:15]2[C:16]3=[C:17]4[C:18](=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[C:6]4[CH:5]=[CH:4][C:3]3=[CH:1][CH:2]=1
Reactant: C=Cc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2ccc3cccc4ccc1c2c34

Procedure:
The procedure used to prepare 1-vinylpyrene was similar to that of K. Tanikawa, T. Ishizuka, K. Suzuki, S. Kusabayashi, and H. Mikawa, Bull. Chem. Soc. Japan, 41, 2719-2722, (1968) Under an argon atmosphere, methyltriphenylphosphonium bromide (0.16 mole) was mixed with butyllithium (0.16 mole of 2.0 M butyllithium in pentane) in dry ether (660 ml.). After the ylid color was obtained (4-8 hr.), pyrene-1-carboxaldehyde (0.14 mole) in dry tetrahydrofuran (500 ml.) was added dropwise. The mixture was stirred overnight under an argon atmosphere. Ether was removed by evaporation under reduced pressure, and the remaining tetrahydrofuran solution was boiled under reflux for 1 hour. After evaporation to dryness under reduced pressure, the residue was dissolved in toluene and the resulting solution was washed with 30% aqueous sodium sulfite solution and water. Toluene was evaporated under reduced pressure to precipitate the crude product, which, after dissolving in hot ethanol and treatment with charcoal, allowed 1-vinylpyrene to crystallize as a yellow powder (53% yield), m. p. 88°-89° C. (lit 88°-89° C.). The structure was confirmed by proton NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:22]([NH:28][S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 3,4-dimethoxybenzenesulfonyl chloride (0.500 g, 2.11 mmol), triethylamine (0.750 mL, 5.30 mmol) in 7 mL of ethyl acetate, hexylamine (0.280 mL, 2.11 mmol) was added dropwise and the resulting solution was stirred overnight. The reaction mixture was filtered and the filtrate was washed 1N HCl (2×), dried with MgSO4, filtered and concentrated in vacuo to afford 0.480 g (75%) of N-hexyl-3,4-dimethoxybenzenesulfonamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.46 (m, 1H), 7.32 (m, 1H), 6.94 (m, 1H), 4.22 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 2.93 (q, J=6.4 Hz, 2H), 1.44 (quintet, J=6.9 Hz, 2H), 1.25 (m, 6H), 0.84 (t, J=6.9 Hz, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[Si:23]([O:40][CH2:41][CH:42]([NH:45][C:46]([NH:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1)=[O:47])[CH2:43]O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1>ClCCl>[Si:23]([O:40][CH2:41][C:42]1[NH:45][C:46](=[O:47])[N:48]([CH:49]2[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]2)[CH:43]=1)([C:36]([CH3:39])([CH3:37])[CH3:38])([C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(CO)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[nH]c2=O)CC1
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Dess-Martin periodinane (53 mg, 0.126 mmol) was added to a solution of tert-butyl 4-[({[2-{[tert-butyl(diphenyl)silyl]oxy}-1-(hydroxymethyl)ethyl]amino}carbonyl)amino]piperidine-1-carboxylate (50 mg, 0.090 mmol) in dichloromethane (20 mL) at 0° C. After 4 h, the reaction was quenched with a 1:1 mixture of saturated sodium thiosulfate and sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated. Purification by silica gel chromatography (100% dichloromethane→9% methanol {1% ammonium hydroxide)/dichloromethane} gave the title compound (25 mg). MS 536.3 (M+1)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[O:11]([CH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1)[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1>O1CCCC1>[O:11]([CH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24][C:7]([C@@H:5]2[CH2:4][S:3][C:2](=[O:1])[NH:6]2)=[O:9])[CH2:19][CH2:18]1)[N+:12]([O-:14])=[O:13]
Reactant: NC[C@H]1CC[C@H](CCO[N+](=O)[O-])CC1
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](C(=O)NC[C@H]2CC[C@H](CCO[N+](=O)[O-])CC2)CS1

Procedure:
In 20 ml of anhydrous tetrahydrofuran was suspended 191 mg of (4R)-2-oxo-4-thiazolidinecarboxylic acid and 294 mg of trans-4-(2-nitroxyethyl)cyclohexylmethylamine hydrochloride, and 0.54 ml of triethylamine and 0.28 ml of diphenylphosphoric azide were added thereto with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=1/3) and recrystallizated from dichloromethane-diisopropyl ether to obtain 200 mg of the desired compound as a colorless crystalline solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].CN(C=O)C>O>[C:10]1([C:5]2([CH2:4][CH2:3][CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[O:9][CH2:8][CH2:7][O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCC1(c2ccccc2)OCCO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCC1(c2ccccc2)OCCO1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
Add 2-(3-chloropropyl)-2-phenyl-[1,3]dioxolane (38 g, 168 mmol) and potassium phthalimide (34.2 g, 184.4 mmol) to DMF (80 mL) and stir for 40 min at 150° C. Cool the reaction to RT, dilute with water (1 L) and extract the mixture with a mixture of EtOAc (500 mL) and hexanes (500 mL) and DCM (2 L). Dry (sodium sulfate), concentrate and recrystallize the solid from hot ethanol (600 mL). Filter and dry the residue under vacuum to isolate the title compound as a white solid (47.62 g, 84%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][N:19]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([O:38]CC)=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][N:19]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)(=[O:27])=[O:26])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3cc(F)c4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(-c4ccc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc(F)c3C2)cc1
Yield: 98.9 %

Procedure:
In 3.3 ml of ethanol was suspended 0.33 g of ethyl 1-cyclopropyl-7-[7-fluoro-2-(p-toluenesulfonyl)-isoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, followed by adding thereto 3.3 ml of a 1N aqueous sodium hydroxide solution and 3.3 ml of dioxane, and the resulting mixture was stirred at 40° C. for 30 minutes. To the reaction mixture was added 3.3 ml of 1N hydrochloric acid and the crystals were collected by filtration to obtain 0.31 g of colorless 1-cyclopropyl-7-[7-fluoro-2-(p-toluenesulfonyl)isoindolin-5-yl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[C:6]([NH:14][CH:15]([CH3:19])[CH:16]([CH3:18])[CH3:17])[N:5]2[N:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[C:4]2[N:3]=1.[CH2:26](OC(OCC)CCl)[CH3:27]>C(O)C>[Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[C:6]([NH:14][CH:15]([CH3:19])[CH:16]([CH3:18])[CH3:17])[N:5]2[N:20]=[CH:21][C:22]([C:23]3[O:24][CH:26]=[CH:27][N:25]=3)=[C:4]2[N:3]=1
Reactant: Cc1ccsc1-c1c(Cl)nc2c(C(N)=O)cnn2c1NC(C)C(C)C
Reactant: CCOC(CCl)OCC
Solvent: CCO
Product: Cc1ccsc1-c1c(Cl)nc2c(-c3ncco3)cnn2c1NC(C)C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
0.95 g (2.5 mmol) of 5-chloro-7-(1,2-dimethylpropylamino)-6-(3-methylthiophen-2-yl)pyrazolo-[1,5-α]pyrimidine-3-carboxamide was dissolved in 25 ml of ethanol, and 1.0 g (6.5 mmol) of chloroacetaldehyde diethyl acetal was added. The mixture was stirred for 3 hours at 120° C. and 15 bar in a microwave oven (200 W). The reaction mixture was then concentrated under reduced pressure, and the residue that remained was chromatographed on silica gel using a mixture of cyclohexane:ethyl acetate=1:1. This gave 0.3 g of [5-chloro-6-(3-methylthiophen-2-yl)-3-oxazol-2-yl-pyrazolo[1,5-α]pyrimidin-7-yl](1,2-dimethylpropyl)amine (logPs=4.3; content according to HPLC: 98%)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])(=O)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(N2CCC3(CC2)OCCO3)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (2.47, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and diethyl malonate (2.0 g, 12.5 mmol) in toluene (100 mL) containing a catalytic quantity of piperidinum acetate was refluxed for 18 hours. After cooling to room temperature the solution was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel using ethyl acetate/hexanes as the eluent gave the title compound as a yellowish gum; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3 H), 1.29 (t, J=7.1 Hz, 3 H), 1.79 (t, J=5.8 Hz, 4 H), 3.46 (t, J=5.8 Hz, 4 H), 4.27 (q, J=7.1 Hz, 2 H), 4.31 (q, J=7.1 Hz, 2 H), 6.85 (d, J=8.9 Hz, 2 H), 7.33 (d, J=8.9 Hz, 2 H), 7.61(s, 1 H); MS (ES) m/z: 390.0 (MH+); HRMS Calcd. for C21H27NO6(MH+): 390.1911. Found: 390.1910.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([CH:32]=[CH:31][CH:30]=[C:28]([OH:29])[CH:27]=1)[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:26][C:25]4[CH:27]=[C:28]([OH:29])[CH:30]=[CH:31][CH:32]=4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(O)c4)c23)cc1

Procedure:
Heat 500 mg (1.49 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 654 mg (5.94 mmol) of resorcinol and 726 mg (2.23 mmol) of caesium carbonate in 10 ml of DMF to 120° C. for 2 h. After cooling, filter and purify the filtrate directly by means of preparative HPLC. Stir the resulting product with dichloromethane, filter with suction, wash with dichloromethane and dry under reduced pressure. 171.4 mg (27% of theory) of the target product are obtained as a beige solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:40].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:40]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar and charged with tert-butyl 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (8.42 g, 13.0 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (15.0 mL, 195 mmol). The solution was stirred at room temperature for 2 h. The solution was diluted with toluene (20 mL) and then concentrated in vacuo to afford crude 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid as a solid foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.[H-].[Na+].O>CN1CCCC1=O>[CH3:14][C:4]1[CH:5]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[N:7]=[C:2]([O:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1cc(Cl)nc(-c2n[nH]c(=O)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(-c2n[nH]c(=O)[nH]2)c1
Temperature: 140 °C

Procedure:
A mixture of 3-(6-chloro-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (428 mg, 2.032 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (457 mg, 2.439 mmol) and sodium hydride (81 mg, 2.032 mmol) in N-methyl-2-pyrrolidinone (7 mL) was heated in a microwave reactor at 140° C. for 30 minutes. After cooling, water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1M HCl aq and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound, which was used without further purification. ESI-MS [M+H-tert-butyl]+ 306.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.C(#N)C.[H-].[Na+].[C:26](OC=O)(=[O:28])C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:26]=[O:28])=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: CN1CC([N+](=O)[O-])=C(NCc2ccc(Cl)nc2)N(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1CC([N+](=O)[O-])=C(N(C=O)Cc2ccc(Cl)nc2)N(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a mixture of 0.27 g of 4-(6-chloro-3-pyridylmethylamino)-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 13), 5 ml of dry THF and 5 ml of dry acetonitrile was added 0.0239 g of sodium hydride (60%, in oil) in small portions over 1 minute with ice cooling. After the mixture was stirred at room temperature for 30 minutes, a solution of 0.24 g of formic acetic anhydride in 1 ml of THF was added dropwise over a period of 4 minutes with ice cooling and the mixture was then stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (20:1)) to give 0.14 g of 4-[N-(6-chloro-3-pyridylmethyl)-N-formylamino]-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 30) as a syrup.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH3:16])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[F:19][C:20]([F:36])([F:35])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH3:16])[C:32](=[O:34])[CH2:31][CH2:30][C:29]#[C:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:36])[F:35])=[CH:27][CH:26]=2)=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNC)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(C)C(=O)CCC#Cc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
In analogy to the procedures described in example 29A], 2-methyl-2-(4-methylaminomethyl-phenoxy)-propionic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) to give the title compound as light brown oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([O:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C>C1COCC1>[CH2:48]([C@@:25]1([O:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]1=[O:45])[CH:46]=[CH2:47]
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (495 mg, 0.749 mmol; Example 203, Step B) in THF (7.49 mL) was sparged with argon for 5 minutes and cooled to 0° C. 1.0 M lithiumdiisopropylamide solution in THF (1.461 mL, 1.461 mmol) was added dropwise. The internal temperature did not rise above 2° C. After 30 minutes, allyl bromide (0.194 mL, 2.247 mmol) was added. The cooling bath was replaced with a room temperature water bath. After 70 minutes, the mixture was quenched with sat. aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (40 g column, eluent: 5 to 30% ethyl acetate/hexanes) to afford the title compound as the more polar diastereomer.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)CCC>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[N:19]3[C:15]([S:16][CH:17]=[CH:18]3)=[N:14][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Reactant: Nc1nccs1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nc2sccn2c1-c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (1 g, 4 mmol) in n-butanol (3 ml) was added in a single portion to a hot (110° C.), stirred solution of 2-aminothiazole in n-butanol (3 ml). After refluxing for 2 hours, triethylamine (0.5 ml, 4 mmol) was added and heating was resumed for a further 2 hours. All volatiles were evaporated and the residue was chromatographed on silica gel, eluting with ethyl acetate:hexane:diethylamine (5:14:1) to afford an off-white solid (0.34 g, 35%), m.p. 88°-91° C.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.Br[CH2:11][O:12][CH2:13][CH3:14].[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][NH:26][CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1>CN(C)C=O>[NH3:4].[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][N:26]([CH2:14][CH2:13][O:12][CH3:11])[CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH2:30][CH2:29]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CCOCBr
Solvent: CN(C)C=O
Product: COCCN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Product: N
Temperature: 80 °C
Reaction time: 18 h
Yield: 33.2 %

Procedure:
N,N-Diisopropylethylamine (80 μl, 0.62 mmol), followed by 2-bromomethoxyethane (0.2 ml, 0.62 mmol) were added to a solution of the amine from example 12 (200 mg, 0.52 mmol) in N,N-dimethylformamide (6 ml) and the reaction mixture was stirred at 80° C. for 18 hours. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (95:5:0.5) to give the title compound as a gum (76 mg).