Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-:12].[NH2:13][N:14]1[CH:18]=[CH:17][N+:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[C:15]1[CH2:30][CH3:31]>C(O)(=O)C>[Cl-:12].[CH3:29][N:27]([CH3:28])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]=[N:19][N+:16]2[CH:17]=[CH:18][N:14]([N:13]=[CH:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:15]=2[CH2:30][CH3:31])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCc1n(N)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc([N+](=O)[O-])cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.61 g (4 mmol) of p-nitrobenzaldehyde is added to a solution of 1.19 g (4 mmol) of 3-amino-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride in 10 ml of glacial acetic acid, the mixture is stirred at room temperature for 16 hours and the product is precipitated by the addition of ether. The product is then filtered off and recrystallized from ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethyl-3-[(p-nitrobenzylidene)amino]imidazolium chloride of melting point 250°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([O:33][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Si:34]([O:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[CH3:32])[CH2:25][C@@H:9]1[CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:12][CH2:13][NH:8]1)([C:47]([CH3:48])([CH3:49])[CH3:50])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)OC(C)(C)C)[C@H](Cc3ccc(C)c(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)C2)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H]1CN(CCN2CCN[C@H](Cc3ccc(C)c(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)C2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution of (2R)-1-tert-butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-methoxymethylmorpholino]ethyl]piperazine (13.43 g) in dichloromethane (67.0 ml) was added trifluoroacetic acid (67.0 ml) at 0° C. After stirring at room temperature for 30 minutes, the mixture was concentrated and was added dropwise saturated aqueous sodium hydrogen carbonate solution. After stirring at room temperature for 30 minutes, the mixture was extracted with dichloromethane (100 ml×1, 50 ml×2). The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure to give (2R)-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)-4-[2-[(2S)-2-methoxymethylmorpholino]ethyl]piperazine (11.63 g) as a brown oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[C@@H:15]([O:42][CH3:43])[C@H:16](O)[C:17]1[C:22]2[S:23][CH:24]=[CH:25][C:21]=2[C:20]([O:26][CH2:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[C@@H:15]([O:42][CH3:43])[CH2:16][C:17]1[C:22]2[S:23][CH:24]=[CH:25][C:21]=2[C:20]([O:26][CH2:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
The above prepared (S)-4-benzyl-3-((2S,3R)-3-hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionyl)-oxazolidin-2-one (0.255 g, 0.42 mmol) was dissolved in 2.2 ml of trifluoroacetic acid, treated at 0° with 0.663 ml of triethylsilane (10 eq.) and then kept for 3 h at ambient temperature, when TLC indicated the disappearance of starting material. The reaction mixture was poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water and brine (pH of aq. phase˜8), dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) delivered 0.196 g of the title compound as colorless foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:36])=[O:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)O)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(N)=O)cc12
Yield: 92.4 %

Procedure:
A solution 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (0.89 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.61 g, 4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.82 g, 93.2%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[OH:24])=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][CH2:39][CH3:40]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[O:24][CH2:38][CH2:39][CH3:40])=[O:4]
Reactant: CCCBr
Reactant: COC(=O)C1Cc2cc(Br)ccc2CN1C(=O)c1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1c(C)cccc1C(=O)N1Cc2ccc(Br)cc2CC1C(=O)OC
Temperature: 79 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A 100 mL round bottom flask which contains 6-bromo-(2-hydroxoxy-3-methyl-benzoylamino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (373, 0.39 g, 0.932 mmol) and a stirring bar is charged with dry DMF (10 mL). Stirring is initiated. K2SO4 (0.258 g, 1.86 mmol), KI (1 mg, 6 μM), and 1-bromopropane (0.2 mL, 2.24 mmol) are added in turn. The reaction flask is immersed in an oil bath and fitted with a reflux condenser. The oil bath is heated to 79° C. The reaction is stirred for 2 h at this temperature then the oil bath is turned off. After 16 h at ambient temperature, heating is reinitiated at 53° C. for an additional hour. Analysis by ttlc (silica, 1:1 EtOAc:Heptanes), indicates consumption of starting material and appearance of a spot with a slightly lower Rf. The reaction is again allowed to cool to ambient temperature and filtered through a bed of Celite. The resulting solution is diluted with EtOAc (60 mL) and washed repeatedly with brine (4×40 mL), and then dried over MgSO4, filtered and evaporated by pumping to a constant weight yields light yellow oil (0.42 g, 98%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:9][C:7]1([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3](=[O:18])[CH:2]([NH:1][C:19](=[O:21])[CH3:20])[CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Product: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and acetic anhydride in an analogous manner to Example 1271d as a white solid. (420 mg, 90%), HPLC 99% purity, HNMR (DMSO) 10.21 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 4.28-4.21 (m, 1H), 2.23-2.17 (m, 1H), 2.02-1.95 (m, 1H), 1.81 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)(=O)C.CO>[O:8]1[CH2:13][CH2:12][CH:11]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH2:10][CH2:9]1
Reactant: O=C1CCOCC1
Reactant: OC1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) were dissolved in titanium(IV) isopropoxide (30 mL) and the reaction was stirred at room temperature overnight. Methanol (40 mL) was added and the reaction was cooled to 0°. NaBH4 (3.8 g) was added in several portions over one hour. After two hours 1N aqueous NaOH was added, followed by ethyl acetate addition. After filtration through celite, the layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4. The crude material was purified by column chromatography using CH2Cl2 with 5-10% 7NNH3 in methanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[NH2:10][NH2:11]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:10][NH2:11])[CH2:4][CH2:3]1
Reactant: NN
Reactant: CN1CCC(=O)CC1
Solvent: O
Solvent: CO
Product: CN1CCC(=NN)CC1

Procedure:
1-Methyl-piperidin-4-one (22.6 g, 0.2 mol) and methanol (200 mL) were charged to a 500 mL three-necked flask fitted with an addition funnel. The vessel was cooled in an ice bath and kept under a nitrogen atmosphere while a solution of hydrazine monohydrate (5 g, 0.1 mol) in 50 mL of methanol was added drop-wise over a period of one hour. A white precipitate formed after about half of the hydrazine was added. Stirring was continued overnight, and subsequent TLC indicated one product. The methanol was removed in vacuo, and the residue was slurried in hexane and filtered to provide N,N′-bis-(1-methyl-piperidin-4-ylidene)-hydrazine. 1H NMR (300 MHz, CDCl3)δ(ppm): 2.6 (m, 8H), 2.5 (m, 8H), 2.33 (s, 6H).
Reaction SMILES: O[C:2]1([CH2:26][O:27][CH3:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:35])CC>ClCCl>[F:35][C:2]1([CH2:26][O:27][CH3:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Solvent: ClCCl
Product: COCC1(F)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 68 %

Procedure:
The title compound was prepared by reacting ((S)-N-{3-[4-(4-hydroxy-4-methoxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with DAST (4.10 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 68% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:29])[CH:27]=[CH2:28]>>[CH2:31]([O:30][C:26]([CH2:27][CH2:28][N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(=O)OCc1ccccc1
Product: O=C(CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1)OCc1ccccc1
Yield: 45 %

Procedure:
3.5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are heated under reflux with 4 g of benzyl acrylate for 5 hours. The hot solution is filtered, and the precipitate which separates out is filtered off under suction, washed with ethanol and dried. 2.3 g of 7-[4-(2-benzyloxycarbonyl-ethyl)-piperazin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 132°-135° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]([CH2:27]C)[CH2:25][CH3:26]>>[CH3:23][CH:24]([CH3:27])[CH2:25][CH2:26][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CCC(CC)CBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)CCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 132 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(bromomethyl)pentane and conditions outlined in procedure V. M.p.=143-146° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (d, 1H), 7.75 (d, 2H), 7.55 (m, 1H), 3.05 (s, 2H), 2.7 (d, 2H), 2.35-2.2 (m, 4H), 1.95 (d, 2H), 1.8-1.7 (d, 2H), 1.6-1.5 (m, 1H), 1.35-1.25 (m, 2H), 0.9-0.8 (m, 6H); LCMS: 372 [M+H].
Reaction SMILES: [F:1][C:2]([F:20])([CH2:17][CH2:18][CH3:19])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:22][CH:23]([CH2:34][CH3:35])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:33][CH2:32]2)[N:27]=1)[OH:25].C(NC(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH:31]1([C:28]2[N:27]=[C:26]([CH:24]([OH:25])[CH:23]([NH:22][C:5]([CH:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:20])[CH2:17][CH2:18][CH3:19])=[O:7])[CH2:34][CH3:35])[O:30][N:29]=2)[CH2:32][CH2:33]1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(C2CC2)no1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCCC(F)(F)CC(NC(=O)N1CCOCC1)C(=O)NC(CC)C(O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (104 mg, 0.35 mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (86.7 mg, 0.37 mmol) and diisopropyl amine (219 mg, 0.42 mmol) in dry dichloromethane (5 mL) is added PyBOP (113 mg, 0.87 mmol). The mixture is stirred at room temperature for 16 hr and the evaporated in vacuum. The residue is diluted with ethyl acetate (25 mL) and washed with saturated NaHCO3 (30 mL), dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (2:1 then 1:0) to afford morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (146 mg, 88%) as a solid. LC/MS shows 2 isomers, total 100% M+1 474.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:19][CH2:16][CH:17]=[CH2:18])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: C=CCN
Solvent: CCCCC
Product: C=CCNC(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 9.6 grams (.0416 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 10° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.37 grams (.0416 moles) of allylamine. The reaction mixture became viscous, was diluted with pentane and stirred for 24 hours at room temperature. The pentane was stripped from the reaction mixture to leave an orange liquid weighing 11.3 grams (94% crude yield). The infrared spectrum of the product had a strong band at 1525 cm-1 and a sharp NH band at 3300 cm-1 and the isothiocyante band at 2040 cm-1 was very weak indicating a trace of the starting material was still present.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].[I-].[Na+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>COCCOC>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCCl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2(3-chloropropoxy)-1-methoxy-4-nitrobenzene, (100 g, 0.407 mol) and sodium iodide (9.2 g, 0.614 mol) was added to 520 mL of dry 1,2-dimethoxyethane. To the mixture was then added N-methylpiperazine (82 g, 0.814 mol). Stirred and heated the reaction to reflux. The reaction was monitored by HPLC. After 8 hours, the heating mantle was removed and the reaction was allowed to cool to ambient temperature. The reaction mixture was then drowned in 1 L of ethyl acetate and stirred for a minimum of 1 hour. Bright yellow solids precipitated. The mixture was filtered and rinsed and the salts collected with ethyl acetate. The filtrate was washed once with 400 mL of 0.5 N NaOH. The layers were separated and the organic layer was washed with water (3×390 mL). The combined organic layers were concentrated under vacuum at 35-40° C. to obtain 97.8 g (light orange oil) (77%); 1H NMR (300 MHz, CDCl3) δ 7.91 (dd, J=2.6, 9 Hz, 1H), 7.77 (d, J=2.6 Hz, 1H), 6.90 (d, J=9 Hz, 1H), 4.14 (t, J=7 Hz, 2H), 3.96 (s, 3H) 2.54 (t, J=7 Hz, 2H), 2.48 (m, 8H), 2.30 (s, 3H), 2.06 (m, 2H); MS (ES) m/z310.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH2:28][NH:29][C:30](=[N:38][C:39]#[N:40])OC5C=CC=CC=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.CC(O)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C1COCC1>[C:39]([NH:38][C:30]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[N:29][CH2:28][C:27]#[C:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]2)#[N:40]
Reactant: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N#CNC(=NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)N1CCOCC1
Temperature: 80 °C
Yield: 20.1 %

Procedure:
Material from step F (9 mg, 0.016 mmol) is placed in a reaction vial and dissolved in 2 ml of a 1:1 THF:i-PrOH mixture. Morpholine (0.08 mmol) is added at r.t, and the sealed vial is heated in an oil bath at 80° C. Reaction progress at 80° C. is followed by LC/MS, and the reaction is stopped after reaching 90% conversion (3 hours). Chromatography of the crude on silica (MeOH/EtOAc) affords pure desired product (1.8 mg, 20%). MS ESI (+) m/z 560 (M+1) detected; 1H NMR (400 MHz, deuterated acetone containing 10% deuterated methanol) δ 8.58 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.84-7.76 (m, 4H), 7.65 (d, 1H), 7.37 (q, 1H), 7.12 (d, 1H), 7.04 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[K+].Cl>CS(C)=O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 6-chloropyridine-3-carboxylic acid (6.0 g, 38.1 mmol), 2,2,2-trifluoroethanol (8.2 mL, 114.2 mmol) and potassium hydroxide (10.7 g, 190.4 mmol) in DMSO (50 mL) was stirred at 120 C for 18 h and left standing at room temperature for 2 days. A further 2 equivalents of potassium hydroxide and 1.5 equivalent of 2,2,2-trifluoroethanol were added and the reaction mixture was stirred at 120 C for 18 h. The mixture was acidified with a concentrated aqueous solution of HCl until a cream precipitate appeared. The precipitate was collected by filtration, washed with a 1N aqueous solution of HCl before being dissolved in EtOAc, washed 3 times with a 1N aqueous solution of HCl and 3 times with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound as a cream solid (6.9 g, 82%). Method C HPLC-MS: MH+ requires m/z=222 Found: m/z=222, Rt=1.24 min (98%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([Cl:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(Cl)c1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(Cl)cccc2c1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide (780 mg, 2.30 mmol) in THF (20 mL) was treated with bis(trichloromethyl) carbonate (1.02 g, 3.45 mmol) and the solution stirred at room temperature for 21 h. The mixture was diluted with DCM and washed sequentially with saturated aqueous NaHCO3, water and brine. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 25-50%), to give 3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione as a white solid (800 mg, 95% yield). Mass spectrum m/z 365, 367 (M+H)+.
Reaction SMILES: [C:1]([C@@:3]1([CH:35]([CH3:37])[CH3:36])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:34])#[N:2].[ClH:38]>O>[ClH:38].[C:1]([C@@:3]1([CH:35]([CH3:37])[CH3:36])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:34])#[N:2]
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C4(C(=O)OC(C)(C)C)CCOCC4)cc3)n2)C1=O
Agent: Cl
Solvent: O
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C4(C(=O)O)CCOCC4)cc3)n2)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl 4-(4-((4-((3S)-3-cyano-3-isopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)phenyl)tetrahydro-2H-pyran-4-carboxylate (30 mg) obtained in Example 299 in water (5.0 mL) was added 2 M hydrochloric acid (3.0 mL), and the mixture was stirred at 100° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized (diisopropyl ether/ethyl acetate) to give the title compound (7.5 mg).