Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>CC#N.C(O)(C(F)(F)F)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Oc1ccc(Cl)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.7 %

Procedure:
3-Phenoxyphenol (1.00 g, 5.4 mmol) was dissolved in MeCN (40 mL) and TFA (0.5 mL). N-Chlorosuccinimide (717 mg, 5.4 mmol) was added and the reaction stirred at ambient temperature for 48 h. Solvents were removed in vacuo to afford the crude product as an oil (2.15 g). 300 mg of this crude material was purified by HPLC to afford in order of elution 4-chloro-3-phenoxyphenol (68 mg, 0.31 mmol, 41%) M.S. (ESI) (m/z): 219,221 [M−H]−; and 6-chloro-3-phenoxyphenol (73 mg, 0.33 mmol, 44%) M.S. (ESI) (m/z): 219,221 [M−H]−.
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[NH2:21][C:22]([CH:26]([F:28])[F:27])=[CH:23][C:24]#[N:25]>C(O)(=O)C.C(O)CCC>[C:24]([C:23]1[CH:1]([C:3]2[O:11][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=3[CH:4]=2)[C:23]([C:24]#[N:25])=[C:22]([CH:26]([F:28])[F:27])[NH:21][C:22]=1[CH:26]([F:28])[F:27])#[N:25]
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#CC=C(N)C(F)F
Solvent: CCCCO
Solvent: CC(=O)O
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1cc2c(NC(=O)c3ccccc3)nccc2o1

Procedure:
A solution of 200 mg (0.75 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A) in acetic acid (1.3 ml) was treated with a solution of 200 mg (1.69 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 1-butanol (1.0 ml). The mixture was heated to reflux temperature for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aq. sodium bicarbonate solution. The organic layer was separated, washed with brine and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 100% methanol) yielding 28 mg (8% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][O:19][CH:20]([O:26][CH3:27])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+].[Na]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:21]([CH:20]([O:26][CH3:27])[O:19][CH3:18])[C:22]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)CC(OC)OC
Reactant: O=Cc1cccnc1Nc1cc(Cl)cc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A solution of 42.7 g of 2-(3,5-dichlorophenyl)aminonicotinaldehyde, prepared in Example 29, in 500 ml of tetrahydrofuran containing 35.6 g of methyl 3,3-dimethoxypropionate, and a solution of sodium methylate prepared from 5.5 g of sodium in 100 ml of methanol, are stirred for 24 h at room temperature. The reaction mixture is subsequently concentrated under vacuum, water is then added and the crystals formed are filtered off, washed carefully with water and dried to give 44.25 g of 1-(3,5-dichlorophenyl)-1,2-dihydro-3-dimethoxymethyl-2-oxo-1,8-naphthyridine in the form of white crystals melting at 190° C. Yield 75.7%.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1.[NH3:17]>C(O)C>[NH2:17][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: c1cc(-c2csnn2)ccc1OCC1CO1
Reactant: N
Solvent: CCO
Product: NCC(O)COc1ccc(-c2csnn2)cc1
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 4-[4(2,3-epoxypropoxy) phenyl]-1,2,3-thiadiazole in 10 ml. of anhydrous ethanol is saturated with ammonia and the reaction mixture is maintained at room temperature for 16 hours. The reaction mixture is then evaporated to dryness under vacuo, to yield the crude 4-[4(3-amino-2-hydroxypropoxy)phenyl]-1,2,3-thiadiazole, which can be further purified by thin layer chromatography.
Reaction SMILES: C(O)(C)C.[C:5]([O:9][C:10](=[O:23])[NH:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)([CH3:8])([CH3:7])[CH3:6].[O:24]1[CH2:26][C@H:25]1[CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>O>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH2:27][C@@H:25]([OH:24])[CH2:26][N:18]2[CH2:17][CH:16]3[O:22][CH:20]([CH2:21][N:14]([CH2:13][CH2:12][NH:11][C:10](=[O:23])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:15]3)[CH2:19]2)=[CH:30][CH:31]=1)#[N:34]
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Temperature: 66 °C
Yield: 99.4 %

Procedure:
iso-Propanol (5 mL) and water (0.5 mL) were added to [2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester (see Example 3 (Alternative I) above; 0.43 g, 1.6 mmol) and 0.4-[(2S)-oxiranylmethoxy]benzonitrile(0.280 g, 1.6 mmol; see Preparation D above) was added. The mixture was heated at 66° C. for 19 hours (reaction was complete in 2 hours). The solvent was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.71 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cccc(NC(C)=O)c1)c1ccccc1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
N-(3-Aminophenyl)acetamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 mL, 1.64 mmol), and DIPEA (0.43 mL, 2.47 mmol) are dissolved in acetonitrile (5 mL). The reaction is heated under MW irradiation at 100° C. for 30 minutes. Conversion complete by UPLC/MS-UV. Acetonitrile is evaporated and the crude residue is purified by flash chromatography (DCM/EtOAc=8/2) to obtain intermediate I92 as a colorless oil (440 mg, 86% yield).
Reaction SMILES: [OH-:1].[K+].CO.O.[CH3:6][C@@H:7]([C@@H:14]1[C@@:18]2([CH3:35])[CH2:19][CH2:20][C:21]3[C@@:26]4([CH3:34])[CH2:27][CH2:28][C@H:29]([OH:33])[C:30]([CH3:32])([CH3:31])[C@@H:25]4[CH2:24][CH2:23][C:22]=3[C@:17]2([CH3:36])[CH2:16][CH2:15]1)[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12]>CCCCCC.CCOCC>[CH3:13][C:11]([CH3:12])=[CH:10][CH2:9][CH2:8]/[C:7](/[CH3:6])=[CH:14]/[CH2:15][CH2:12]/[C:11](/[CH3:13])=[CH:10]/[CH2:9][CH2:8]/[CH:7]=[C:14](/[CH2:18][CH2:35]/[CH:16]=[C:17](/[CH2:18][CH2:19][CH:20]1[O:1][C:21]1([CH3:22])[CH3:26])\[CH3:36])\[CH3:15].[CH3:6][C@@H:7]([C@@H:14]1[C@@:18]2([CH3:35])[CH2:19][CH2:20][C:21]3[C@@:26]4([CH3:34])[CH2:27][CH2:28][C@H:29]([OH:33])[C:30]([CH3:32])([CH3:31])[C@@H:25]4[CH2:24][CH2:23][C:22]=3[C@:17]2([CH3:36])[CH2:16][CH2:15]1)[CH2:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13]
Reactant: [OH-]
Agent: CC(C)=CCC[C@@H](C)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC1OC1(C)C

Procedure:
After 1 hour at 37° C. the reaction was stopped by the addition of 0.6 ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1, v/v) which contained 25 μg of non-radioactive MOS and 25 μg of lanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v) was added to each test tube, these were again shaken and then centrifuged. The upper phase was transferred into a glass test tube, the lower phase was again extracted with hexane:ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen, the residue was suspended in 50 μl of hexane:ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS substrate and the lanosterol product were 0.91 and, respectively, 0.54. After drying, radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the yield of the reaction and OSC inhibition.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[C:7]3[CH:15]=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[Br:18]Br>O>[Br:18][C:15]1[C:7]2[C:6]3[CH:5]=[C:4]([O:16][CH3:17])[C:3]([O:2][CH3:1])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[NH:13][N:14]=1
Reactant: BrBr
Reactant: COc1cc2ncc3[nH]ncc3c2cc1OC
Solvent: O
Product: COc1cc2ncc3[nH]nc(Br)c3c2cc1OC
Reaction time: 1 h
Yield: 95 %

Procedure:
7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinoline (500 mg, 2.18 mmol) is dissolved in water (40 ml). Bromine (220 μl, 4.36 mmol) is subsequently added dropwise at room temperature with exclusion of light. The reaction solution is then stirred for 1 h. When the reaction is complete, the mixture is evaporated to dryness in vacuo, giving 1-bromo-7,8-dimethoxy-3H-pyrazolo[3,4-c]quinoline (752 mg, purity 85%, 2.07 mmol) as a solid. MS: 308.0/310.0 (M+H+, monobromo isotope distribution), TLC (HPTLC): Rf=0.50 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH:33]1[C:38](Cl)=[N:37][C:36]([NH2:40])=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:34]5[CH:33]=[CH:38][N:37]=[C:36]([NH2:40])[N:35]=5)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (92 mg, 0.215 mmol), PdCl2(PPh3)2 (15.12 mg, 0.021 mmol), 2-amine-4-chloropyrimidine (30.6 mg, 0.236 mmol) and sodium carbonate (68.3 mg, 0.644 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) and heating in the microwave for 1 h at 120° C. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68-8.80 (1H, m), 8.49 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=5.5 Hz), 7.72-7.99 (4H, m), 7.41 (1H, ddd, J=7.0, 5.1, 2.0 Hz), 7.29-7.34 (1H, m), 6.93 (1H, d, J=5.1 Hz), 6.77-6.86 (1H, m), 5.16 (2H, br. s.), 3.77-3.95 (2H, m), 2.27-2.44 (3H, m), 1.61-1.68 (3H, m), 1.51-1.60 (3H, m). Mass Spectrum (ESI) m/e=478 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[CH2:32](P(=O)(OCC)OCC)[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:32]/[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 54.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.070 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1 to 9:1, v/v) to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.43 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 72-73° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][C:6]3([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]3)[CH2:9]2)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: CN1CCC2(CCNC2)C1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1COc2c(N3CCC4(CCN(C)C4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227°-230° C. (dec).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][P:34]([CH3:38])(=[O:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][P:34]([CH3:38])(=[O:37])[CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ON1C2C=CC=CC=2N=N1.[C:44](O)(=[O:47])[CH2:45][OH:46].Cl.CN(C)CCCN=C=NCC.Cl>CO.[OH-].[Na+].C(#N)C.C(Cl)Cl>[OH:47][CH2:44][C:45]([N:11]1[C:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)=[C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[N:10]1)=[O:46]
Reactant: O=C(O)CO
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: O=C(CO)n1nc(-c2ccc(Cl)cc2)c(-c2ccncn2)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A 1 L round bottom flask was charged with 34.2 g (102 mmol) of 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole, 500 mL of CH2Cl2 and 26.6 mL (153 mmol) of Hunig's base. To this suspension was added 16.5 g (122 mmol) of 1-hydroxybenzotriazole and 8.1 g (106 mmol) of glycolic acid. The addition of glycolic acid was followed by the addition of 23.7 g (122 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated in vacuo to leave an oily residue. The residue was dissolved in 400 mL of methanol and 50 mL of 2.5 N NaOH. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was acidified to pH 5 with 2 N HCl and was extracted with CH2Cl, (6×200 mL). The combined organic phases were filtered through phase paper and the filtrate was concentrated in vacuo to leave a yellow residue. The residue was treated with 75 mL of acetonitrile. A precipitate formed. The solid was filtered and washed with additional acetonitrile and Et2O to afford 31.4 g of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole. 1H NMR (DMSO-d6) 9.20 (s, 1H), 8.67 (d, J=4.8, 1H), 7.40 (m, 4H), 7.17 (d, J=4.0, 1H), 4.53 (m, 2H), 4.13 (s, 2H), 3.77 (m, 1H), 3.05 (t, J=12.7 Hz, 1H), 2.69 (m, 1H), 1.90 (m, 2H), 1.73 (m, 2H); MS (M+H): 398 (base peak).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[CH3:36][NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:39]
Reactant: CN=C=O
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCc2cc(OC)c(OC)cc2C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A stirred solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (487.6 mg, 1.306 mmoles) in methylene chloride (5 mL) at 0° C. was treated with triethylamine (0.24 mL, 1.3 equiv.) and methyl isocyanate (0.10 mL, 1.3 equiv.). The mixture was immediately allowed to warm to room temperature. After 4 hours, the mixture was evaporated and the residue partitioned between ether and 2% phosphoric acid. The organic phase was washed with 1M sodium hydroxide and brine, dried over sodium sulfate, and evaporated to give a solid foam that was triturated with hexane to give the product as a white solid (494.8 mg, 88%). 1H-NMR (CDCl3) δ 2.45 (m, 1H), 2.65-3.10 (m, 3H), 2.73 (s, 3H), 3.38 (m, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 3.90 (m, 2H), 4.03 (t, 1H), 4.45 (m, 1H), 6.38 (s, 1H), 6.58 (s, 1H), 7.32 (m, 10H). Mass spec. 431.2 (MH)+. Anal. Calc. for C27H30N2O3: C-75.32, H-7.02, N-6.51. Found: C-75.04, H-7.13, N-6.35.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCO)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 4-tert-butyloxycarbonyl-1-[2-(tert-butyldimethylsilyloxy)ethyl]-piperazin-2-one (0.88 g, 2.5 mmol) in tetrahydrofuran (30 mL) was added tetrabutylammonium fluoride (3.6 mL, 3.6 mmol, 1.0 M in tetrahydrofuran) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by flash column chromatography (silica gel, eluting with 30% ethyl acetate in hexanes) gave 4-tert-butyloxycarbonyl-1-(2-hydroxyethyl)-piperazin-2-one (0.45 g, 75%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])=[O:4].[CH2:11]=O.Cl>>[O:7]=[C:6]1[N:5]([CH3:10])[C:3](=[O:4])[N:2]([CH3:11])[CH2:1][N:8]1[CH3:9]
Reactant: C=O
Reactant: CNC(=O)N(C)C(=O)NC
Agent: Cl
Product: CN1CN(C)C(=O)N(C)C1=O

Procedure:
145 g (1 mol) of 1,3,5-trimethyl-biuret and 30 g of paraformaldehyde are heated together with 5 ml of concentrated hydrochloric acid 70° C for 5 hours. The liquid contents of the flask are then poured onto a dry metal sheet and, after solidification, the product is recrystallised from cyclohexane. This gives 145 g (98%) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-s-triazine of melting point 88° to 90° C.