Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CCOC(C)=O>[CH3:21][S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 174 (1.327 g, 4.144 mmol) in THF (30 mL) at 0° C. was added TEA (0.6931 mL, 4.973 mmol) and MsCl (0.3528 mL, 4.559 mmol) and the solution stirred for 1 h at 0° C. The mixture was diluted with EtOAc, washed with dilute HCl solution, aq. satd. NaHCO3, and brine, dried (MgSO4) and concentrated to afford 1.51 grams (91%) of (R)-3-(tert-butoxycarbonylamino)-3-(3,4-dichlorophenyl)propyl methanesulfonate (364). The product may contain some of the corresponding chloride.
Reaction SMILES: C([Li])CCC.CCCCCC.CN(C)CCN(C)C.[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[CH:27]1.[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)([C:27]2[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:35])[CH3:20])[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)[OH:44])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(O)(CC2CCCC2)c2ccc(Cl)c(Cl)c2)cc2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
A solution of n-butyl lithium in hexane (2.5 M, 4.5 mL, 11.2 mmol) was treated with N,N,N′,N′-tetramethylethylenediamine (1.69 mL, 11.2 mmol) dropwise, which resulted in a slight exotherm. The resulting yellow mixture was then stirred at room temperature for 15 min. After this time, the mixture was treated with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 138, 3.48 g, 14.0 mmol) dropwise. The resulting mixture was then stirred at room temperature for 30 min and then treated with a solution of 2-cyclopentyl-1-(3,4-dichloro-phenyl)-ethanone (1.8 g, 7.0 mmol) in tetrahydrofuran (8 mL) and then stirred at room temperature for 6 h. After this time, the reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution (25 mL) and it was then stirred over the weekend. The reaction mixture was then extracted with ethyl acetate (2×100 mL) and the combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10% ethyl acetate/hexanes) afforded 2-cyclopentyl-1-(3,4-dichloro-phenyl)-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-ethanol (1.13 g, 32%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1([F:39])[CH2:32][N:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:36]3[CH2:35][CH2:34][CH:33]([N:31]4[CH2:32][C:29]([F:28])([F:39])[CH2:30]4)[CH2:38][CH2:37]3)=[CH:8][C:6]=2[N:7]=1
Reactant: FC1(F)CN(C2CCNCC2)C1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: FC1(F)CN(C2CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-(3,3-difluoroazetidin-1-yl)-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (115 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A solution of 1-(2-(4-fluorophenyl)thiazol-5-yl)ethanol (1.0 g, 4.4 mmol) in dichloromethane (40 mL) was cooled to 0° C. Dess-Martin periodinane (5.7 g, 13.4 mmol) was added slowly at 0° C. and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (80 mL), sodium thiosulfate solution (20 mL), extracted with ether (2×1000 mL), the organic layer dried over Na2SO4, filtered and concentrated to obtain crude product. The crude product was purified by Combiflash® chromatography (40% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)ethanone as off-white solid (820 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.08 (t, 2H), 7.37 (t, 2H), 2.59 (s, 3H); LC-MS m/z calculated for [M+H]+ 222.03. found 222.3.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[C:6](OCC)(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[CH2:3]=[C:2]=[CH:1][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CC[Mg]Br
Reactant: CCCCC(=O)OCC
Solvent: CCOCC
Product: C=C=CC(=O)CCCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.50 moles of propargyl-magnesium bromide in 340 ml. of ether at -78° C. is added a solution of 65.2 g. (0.50 moles) of ethyl valerate in 100 ml. of ether during 60 minutes. The solution is stirred at -78° C. for 30 minutes and then hydrolyzed by pouring onto a mixture of ice and ether. The ether layer is washed with brine, treated with hydroquinone, dried over magnesium sulfate, and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: CC=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccc(C(F)(F)F)cc1
Yield: 71.4 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 4-(trifluoromethyl)benzoic acid (63 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (110 mg, 68%) was obtained as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C.O>[OH:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][C:5](=[O:16])[C:4]([CH2:3][CH2:2][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[C:13]2[CH3:14]
Reactant: Cc1c(CCBr)c(=O)oc2ccc(O)cc12
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCN2CCCC2)c(=O)oc2ccc(O)cc12
Temperature: 25 °C
Yield: 250.9 %

Procedure:
A solution of Example 41A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75° C. for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate was dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica with 10% methanol in dichloromethane to give the titled compound (0.48 g, 25%). MS (DCI) m/z 274 (M+H)+;
Reaction SMILES: C([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#N.Cl.[C:26](=[O:29])(O)[O-:27].[Na+]>C(O)(=O)C>[C:26]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)([OH:27])=[O:29]
Reactant: N#Cc1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C

Procedure:
A solution of 3-(4-cyanobenzyl)-2-(3-pyridyl)indole (5.8 g) in 100 ml of a 1:1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid is heated at reflux for 20 hours. After cooling, the solution is poured into ice water (100 ml) and the pH is adjusted to 4.5-5 with saturated sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the ethyl acetate extract is washed with water and evaporated to dryness to give 3-(4-carboxybenzyl)-2-(3-pyridyl)indole.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][C:10]1([CH3:22])[N:14]([C:15](=[O:18])[CH2:16][NH2:17])[C@@H:13]([CH2:19][CH:20]=[CH2:21])[CH2:12][O:11]1.[N:23]([O-])=O.[Na+]>C(Cl)Cl.O>[N+:17](=[CH:16][C:15]([N:14]1[C@@H:13]([CH2:19][CH:20]=[CH2:21])[CH2:12][O:11][C:10]1([CH3:22])[CH3:9])=[O:18])=[N-:23]
Reactant: O=N[O-]
Reactant: C=CC[C@H]1COC(C)(C)N1C(=O)CN
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC[C@H]1COC(C)(C)N1C(=O)C=[N+]=[N-]
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
{2-[(4S)-2,2-dimethyl-4-(2-propen-1-yl)-1,3-oxazolidin-3-yl]-2-oxoethyl}amine trifluoromethansulfonate D23 (67.0 g) was dissolved in DCM (670 ml) and pH=5 Buffer solution (670 ml) and cooled to 2° C. (internal). Sodium nitrite (26.5 g, 385 mmol) dissolved in water (134 ml) was added dropwise to the reaction mixture stirred at 2° C. over 30 min. The reaction mixture was stirred at 3° C. for 2.5 hours. Phases were separated. Water phase was back-extracted with DCM (1×670 ml, 1×335 ml). The combined organic layers, dried (Na2SO4), were evaporated (bath temperature 30° C.) to give 43 g of crude product. This crude was purified over silica pad [(230-400 Mesh) eluting with Cy/EtOAc 8/2, 7/3, 6/4] to give the title compound D24 (36.58 g) as pale yellow oil. UPLC (Acid GEN_QC): rt=0.59 minutes, peak observed: 210 (M+1) C10H15N3O2 requires 209. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 3 H) 1.69 (s, 3 H) 2.25-2.50 (m, 2 H) 3.43-3.70 (m, 1 H) 3.82-4.01 (m, 2 H) 4.84 (s, 1 H) 5.09-5.24 (m, 2 H) 5.63-5.84 (m, 1 H)
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:53]/[O:54][C:55]([C:58]([OH:60])=[O:59])([CH3:57])[CH3:56])/[C:15]([NH:17][CH:18]2[C:51](=[O:52])[N:20]3[C:21]([C:48]([OH:50])=[O:49])=[C:22]([CH2:25][NH:26][C:27]4[S:31][N:30]=[C:29]([O:32]C(C5C=CC=CC=5)C5C=CC=CC=5)[C:28]=4[C:46]#[N:47])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1>C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:53]/[O:54][C:55]([C:58]([OH:60])=[O:59])([CH3:57])[CH3:56])/[C:15]([NH:17][CH:18]2[C:51](=[O:52])[N:20]3[C:21]([C:48]([OH:50])=[O:49])=[C:22]([CH2:25][NH:26][C:27]4[S:31][N:30]=[C:29]([OH:32])[C:28]=4[C:46]#[N:47])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3snc(OC(c4ccccc4)c4ccccc4)c3C#N)CS[C@H]12)c1csc(N)n1)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3snc(O)c3C#N)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 ml) was added to a suspension of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(4-cyano-3-diphenylmethoxyisothiazol-5-yl)aminomethylceph-3-em-4-carboxylic acid (600 mg) in anisole (2 ml), and the mixture stirred for one hour at ambient temperature. The reaction mixture was evaporated and the residue purified by HPLC eluting with a mixture of MeOH and ammonium carbonate buffer 20:80 v/v. After lyophilisation the title compound was obtained in the form of its ammonium salt (49 mg). NMR in solvent B:--1.5 (s, 3 H); 3.4-3.6 (m, 2 H); 4.1-4.3 (m, 2 H); 5.15 (d, 1 H); 5.8 (d, 1 H); 7.0 (s, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH2:18]>N1C=CC=CC=1>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:1](=[O:5])[CH:2]=[CH:3][CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 19 °C
Reaction time: 12 h

Procedure:
0.24 cm3 of crotonyl chloride is added to 500 mg of 5-(trifluoromethyl)-1H-indazole-3-amine, prepared according to patent U.S. Pat. No. 3,133,081, in 15 cm3 of pyridine. The reaction medium is stirred at about 19° C. for 12 hours and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of tetrahydrofuran, 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed again with 25 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (40/60 by volume) and collecting 25 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 63 mg of N-[5-(trifluoromethyl)-1H-indazol-3-yl]-2-butenamide (E form) are obtained in the form of an off-white solid melting at about 242° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][N:13]1[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]1=[O:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NCCO
Product: CC1=C(C)C(=O)N(CCO)C1=O
Yield: 88.7 %

Procedure:
Analogously to Example 2, 126 g (1 l mol) of 2,3-dimethylmaleic anhydride and 61 g (1 mol) of ethanolamine are reacted to give 150 g of N(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110° C. under 13.3 Pa; yield 89% of theory). The N(2-hydroxyethyl)-2,3-dimethylmaleimide is mixed with 181.5 g (1.78 mols) of acetic anhydride and 3 drops of concentrated sulfuric acid and the mixture is refluxed for one hour in an oil bath heated to 160° C. The acetic acid formed and the acetic anhydride are then distilled off in vacuo. Fractionation of the residue under a high vacuum yields 179 g of N(2-acetoxyethyl)-2,3-dimethylmaleimide (boiling point 104° C./6.66 Pa; yield 95% of theory). The N(2-acetoxyethyl)-2,3-dimethylmaleimide is introduced dropwise, under nitrogen, in the course of 75 minutes into a glass column which is filled with Raschig rings and is heated to 550° C. The pyrolysis products are collected at the lower end of the glass column in a cooled receiver. The yellow oil obtained is taken up in diethyl ether and treated with aqueous sodium bicarbonate solution in order to remove the acetic acid. After drying the organic phase over sodium sulfate, the solvent is removed in vacuo and the product is distilled under a high vacuum. In addition to 39.3 g of unconverted starting material, 84.7 g of (N-vinyl)-2,3-dimethylmaleimide are obtained in the form of a yellowish oil; boiling point 58°-60° C./53.33 Pa; yield: 85% of theory, based on converted starting material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1.CN([CH:18]=[O:19])C.C(N1C=CN=C1)(N1C=CN=C1)=O>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:14][C:18](=[O:19])[N:8]2[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: CCC(CC)Nc1nc(Cl)ncc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
To a microwave vial is added the crude (2-Chloro-5-amino-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 2.329 mmol) and anhydrous DMF (15 ml) followed by 1,1′-carbonyldiimidazole (1.133 g, 6.987 mmol). Sealed vial and microwave heated at 100° C. for 10 min. The reaction mixture is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:1 EtOAC/Hexane) gives the desired product.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:19](=[O:22])[NH:20][N:21]=2)[CH:8]=[C:9]([C:11]2(C(O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:10]=1)([CH3:3])[CH3:2]>CC(O)=O.O>[CH:11]1([C:9]2[N:10]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:6]3[N:7]([C:19](=[O:22])[NH:20][N:21]=3)[CH:8]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)Nc1nc(C2(C(=O)O)CCCC2)cn2c(=O)[nH]nc12
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1nc(C2CCCC2)cn2c(=O)[nH]nc12
Temperature: 25 °C

Procedure:
A solution of 20 mg of 1-(8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-cyclopentanecarboxylic acid in AcOH (3.0 mL) was warmed to 120° C. for 30 min. The reaction was cooled to ambient temperature and diluted with water. The mixture was extracted with EtOAc, the organic layer was washed with water (2×), dried over magnesium sulfate, filtered, and concentrated to leave the title compound as a tan solid. MS (M+H+)=262.3.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]([C@@H:25]4[CH2:29][O:28]C(C)(C)[O:26]4)([CH3:24])[CH3:23])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>CO>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]([CH3:24])([CH3:23])[C@@H:25]([OH:26])[CH2:29][OH:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC[C@@H](C(C)(C)COc2cccc3ccc(-c4nnc5ccccn45)nc23)O1
Agent: Cl
Solvent: CO
Product: CC(C)(COc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](O)CO
Reaction time: 0.5 h
Yield: 95 %

Procedure:
(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)quinoline (0.030 g, 0.072 mmol) was added to 1 N HCl in methanol and stirred for 30 minutes, then evaporated, co-evaporated once in methanol and triturated in DCM to isolate 23 mg of 95% pure desired product as a beige solid. MS ESI (+) m/z 379 (M+1) detected.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)(=O)=O.[NH:28]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:31][N:30]=[N:29]1.[Na]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C@@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C@H:7]([CH2:6][N:29]3[N:30]=[N:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:28]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: COc1cccc([C@H]2[C@H](COS(C)(=O)=O)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cccc(OC)c2)n1
Temperature: 70 °C

Procedure:
A small reaction tube fitted with a screw cap is charged with ((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50 mg, 0.12 mmol) and DMF (1 mL). Ethyl 1H-tetrazole-5-carboxylate, sodium salt (39 mg, 0.24 mmol) is added and the mixture is heated to 70° C. overnight. The cooled reaction is quenched with water, extracted with EtOAc, combined organics are washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (12 g Redisep cartridge, 30-50% EtOAc/hexanes) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.53-7.43 (m, 2H), 7.34-7.28 (m, 3H), 7.10-7.08 (m, 1H), 7.06-7.00 (m, 2H), 6.92-6.90 (m, 1H), 5.67 (d, J=5.3 Hz, 1H), 5.52 (dd, J=(ddd, J=14.6, 6.5 Hz, 1H), 5.47-5.41 (m, 1H), 5.11-4.99 (m, 1H), 4.46-4.41 (m, 2H), 3.76 (s, 3H), 1.39-1.35 (m, 3H); HPLC-MS calculated C21H20ClN5O5 (M+H+) 458.1, found 458.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(4-methoxyphenyl)ethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[CH2:14]([N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:26]([C:24]1[CH:23]=[N:22][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:25]=1)=[O:27]
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3ccccc3)c2)c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 47.6 %

Procedure:
A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (1.6 g, 8.55 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (1.75 g, 8.65 mmol) in methanol (10 ml) were cooled to 0° C. and added EDCI.HCl (2.32 g, 12.11 mmol). The reaction mixture was stirred at 25° C. for 20 hours and the solvents were removed under reduced pressure. To this residue water (10 ml) was added and the precipitate was filtered off, and was washed sequentially with cold water (20 ml) and DCM (25 ml) to obtain 1-Benzyl-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (1.5 g, 47%) as a pale yellow solid.