Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)\[C:35]([CH3:38])([CH3:36])[CH3:37])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(C)(C)C(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccncc2)C(C)(C)C)C1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF (3 mL). Potassium phosphate (424 mg, 2 mmol), copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol) were added. A solution of 4-(1-bromo-3,3-dimethylbut-1-en-2-yl)pyridine (294 mg, 1.5 mmol) in DMF (2 mL) was added dropwise, the reaction mixture was purged with nitrogen, and heated at 85° C. overnight. The DMF was evaporated under reduced pressure and the reaction mixture was diluted with water. The resultant precipitate was filtered and purified by silica gel chromatography (100-200 mesh) using 0-8% MeOH:DCM as eluant. The compound was further purified by HPLC. Yield: 77.03 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.30 (d, 2H), 7.30 (m, 4H), 7.18 (d, 1H), 6.90 (s, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.15 (m, 2H), 3.05 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=[N:3][CH:2]=1.CC1C2O[C@:19]3(C)OC=C[C@H](OC)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)C=CC=[C:36](C)[C:37]([NH:39][C:40]4[C:43](/[CH:46]=N/N5CCN(C)CC5)=[C:44](O)[C:15]([C:16]=2[C:20]3=O)=[C:14]([C:41]=4O)C=1O)=O.[CH3:70][C@@H:71]1[O:75][C@@H:74]([O:76][C@H:77]2[C@H:82]([OH:83])[C@@H:81]([OH:84])[C@H:80]([NH:85][C:86]([NH2:88])=[NH:87])[C@@H:79]([OH:89])[C@@H:78]2[NH:90][C:91]([NH2:93])=[NH:92])[C@H:73]([O:94][C@@H:95]2[O:100][C@@H:99]([CH2:101][OH:102])[C@H:98]([OH:103])[C@@H:97]([OH:104])[C@@H:96]2[NH:105][CH3:106])[C@@:72]1([OH:109])[CH:107]=[O:108].[CH3:110][CH2:111][C@H:112]([NH:115][CH2:116][CH2:117][NH:118][C@H:119]([CH2:122][OH:123])[CH2:120][CH3:121])[CH2:113][OH:114].N1C=CN=CC=1C(N)=O>CO>[CH:1]1[C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=[N:3][CH:2]=1.[CH3:70][C@@H:71]1[O:75][C@@H:74]([O:76][C@H:77]2[C@H:82]([OH:83])[C@@H:81]([OH:84])[C@H:80]([NH:85][C:86]([NH2:88])=[NH:87])[C@@H:79]([OH:89])[C@@H:78]2[NH:90][C:91]([NH2:93])=[NH:92])[C@H:73]([O:94][C@@H:95]2[O:100][C@@H:99]([CH2:101][OH:102])[C@H:98]([OH:103])[C@@H:97]([OH:104])[C@@H:96]2[NH:105][CH3:106])[C@@:72]1([OH:109])[CH:107]=[O:108].[CH3:121][CH2:120][C@H:119]([NH:118][CH2:117][CH2:116][NH:115][C@H:112]([CH2:113][OH:114])[CH2:111][CH3:110])[CH2:122][OH:123].[CH3:73][C:72]([CH3:107])=[CH:71][CH2:4][CH2:5]/[C:6](/[CH3:7])=[CH:1]/[CH2:2][NH:3][CH2:36][CH2:37][NH:39][CH:40]1[CH:41]2[CH2:14][CH:15]3[CH2:16][CH:20]([CH2:19]2)[CH2:46][CH:43]1[CH2:44]3
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CC[C@@H](CO)NCCN[C@@H](CC)CO
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CNCCNC1C2CC3CC(C2)CC1C3
Temperature: -80 °C

Procedure:
Antimicrobial drugs isoniazid, rifampicin, streptomycin, and ethambutol were purchased from Sigma-Aldrich. St. Louis, Mo. Stock solutions of isoniazid, streptomycin, and ethambutol were prepared in distilled and deionized water at 10 mg/mL, sterilized by filtration, and stored frozen at −80° C. Stock solutions of rifampicin, at 1 or 10 mg/mL, were prepared in methanol and stored at −80° C. Pyrazinamide was purchased as the drug reconstituting kit from Becton Dickinson, Cockeysville, Md., and a stock solution was prepared following instructions by the manufacturer. Stock solutions of SQ109 were prepared in methanol at 1 mg/mL and stored at 80° C.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][C:7]=1[C:13](OC)=[O:14])Br.OC1C=CC=CC=1C#N.COC(=O)C(C1C=CC=CC=1C(OC)=O)Br.[OH:43][C:44]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:45]=1[C:46]#[N:47]>>[OH:14][C:13]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[O:43][C:44]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:45]=3[C:46]=2[N:47]=1
Reactant: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Reactant: COc1ccc(O)c(C#N)c1
Agent: COC(=O)c1ccccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: COc1ccc2oc3c4ccccc4c(O)nc3c2c1

Procedure:
The procedure was similar to step S19B, while the starting material 19A and 2-hydroxy-benzonitrile were replaced with 21A and 2-hydroxy-5-methoxy-benzonitrile, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:22][N:23]([CH3:25])[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.69 mmol) and dimethylformamide dimethyl acetal (0.64 mL, 4.8 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. Additional dimethylformamide dimethyl acetal (0.32 mL, 2.4 mmol) was added and heating was continued for an additional 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure (60° C. bath temperature). The dark residue was triturated with methanol and the pale orange solid which formed was collected and dried to give 0.75 g (62%) of 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 228-230° C.; 1H 1H NMR δ 8.19 (d, J=8 Hz, 1H), 7.91 (d, J=12.3 Hz, 1H), 7.71-7.18 (m, 7H), 4.10 (d, J=12.3 Hz, 1H), 2.81 (br s, 6H). Analysis calculated for C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C, 66.20; H, 5.03; N, 12.79.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24]O)[CH:20]=[C:21]([Cl:23])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:24][C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (0.5 g, 2.4 mmol), (3,5-dichloro-phenyl)-methanol (0.84 g, 4.8 mmol), and polymer-supported triphenyl phosphine (1.5 g, 4.8 mmol) in THF (30 mL) in ice-bath was slowly added diisopropyl azodicarboxylate (1.0 mL, 4.8 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(3,5-dichloro-benzyloxy)-phthalic acid dimethyl ester (0.42 g, 48% yield). The product was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([C@@H:10]1[C@@H:14]([CH2:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=2)[CH2:13][NH:12][C:11]1=[O:22])[CH3:9].C([C:25]([O:27][CH3:28])=[O:26])#N>O1CCCC1.CCCCCC>[C:25]([N:12]1[CH2:13][C@H:14]([CH2:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=2)[C@@H:10]([CH2:8][CH3:9])[C:11]1=[O:22])([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C#N
Reactant: CC[C@H]1C(=O)NC[C@@H]1Cc1cncn1C
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)N(C(=O)OC)C[C@@H]1Cc1cncn1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
To a solution of diisopropylamine (58 mg, 0.57 mmol) in tetrahydrofuran (THF) (2 mL) at 0° was added 251 μL of a 2.5 M solution of D-butyl lithium (0.63 mmol) in hexane. The solution was stirred at 0° for 15 min., then cooled to -78° and (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidinone (118.2 mg, 0.57 mmol) in THF (2.5 mL) was added via cannula, followed by a THF (0.5 mL) rinse. After 2 hours at -78 , methyl cyanoformate (50.9 mg, 0.60 mmol) was added and the reaction was maintained at -78° for 1.5 hours, then warmed to room temperature for 15 hours. The reaction was quenched with saturated aqueous NaHCO3, extracted three times with CHCl3, dried (Na2SO4), filtered, concentrated and the residue was chromatographed on silica gel (5% MeOH satured with NH3 /CHCl3) to give 44.3 mg of (3R, 4R)-1-carbomethoxy-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidinone as an oil (28%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH3:3].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.ClCCl.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:2][CH3:3]
Reactant: CCCOCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCOCCCCCC=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
a 50-mL, one-necked, round-bottom flask equipped with a magnetic stirrer was charged with 6-propyloxy-1-hexanol (1.0 g), PDC (4.7 g), dichloromethane (10 mL), Celite (1.0 g), and sodium acetate (100 mg). The reaction mixture was stirred at room temperature under nitrogen for 5 minutes. PDC (4.70 g) was added to the reaction mixture, and stirred overnight. The progress of reaction was monitored by TLC (Note 1). After completion of the reaction, the reaction mixture was directly loaded on the column (230-400 mesh silica gel). A solvent gradient of dichloromethane in ethyl acetate (10-20%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 6-propyloxy-1-hexanal (lot D-1029-050, 710 mg, 71%). Completion of the reaction was monitored by thin layer chromatography (TLC); (eluent: 60% ethyl acetate in hexanes).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][CH:18]([F:27])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:17][CH:18]([F:27])[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:26]=1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(OC(F)F)cc1
Product: CN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(difluoromethoxy)aniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CDCl3): δ 3.28 (s, 3H), 6.15-6.52 (m, 1H), 6.66-6.77 (m, 4H), 7.11-7.27 (m, 5H); Mass Spectrum: M−H+ 379.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cccc(I)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC/C=C/c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The material from Example 1A (2.0 mmol) was dissolved in THF (10 mL). DIBAL-H (1 M in hexane, 6 mL, 6.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 minutes. Saturated sodium potassium tartrate solution was added slowly at 0° C., followed by addition of diethyl ether. The mixture was stirred vigorously overnight. The organic phase was separated and washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound (489 mg). MS (ESI(−)) m/e 259 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.79(t, J=1.7 Hz, 1H), 7.57 (dt, J1=1.7 Hz, J2=7.8 Hz, 1H), 7.45 (dt, J1=1.7 Hz, J2=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.48–6.42 (m, 2H), 4.89 (t, J=5.8 Hz, 1H), 4.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18]O)[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:44]=[N+:45]=[N-:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:44]([CH2:18][CH:10]1[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:24])([F:23])[F:22])[CH:4]=2)([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11]1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=N
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=CCC(CN=[N+]=[N-])CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 51.6 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 38.2 mg, 0.105 mmol) in THF (0.8 mL) was treated sequentially with triphenylphosphine (83 mg, 0.316 mmol), hydrazoic acid (ca. 2M in benzene, 0.211 mL, 0.421 mmol) and diethyl azodicarboxylate (0.050 mL, 0.316 mmol). The resulting mixture was stirred at rt for 19.5 h and then an additional amount of triphenylphosphine (83 mg, 0.316 mmol), diethyl azodicarboxylate (0.050 mL, 0.316 mmol) and hydrazoic acid (ca. 2M in benzene, 0.211 mL, 0.421 mmol) were added. The resulting mixture was stirred for a total of 43 h. After this time, the mixture was concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 5-50% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-4-(azidomethyl)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-6-methylcyclohex-1-enecarboxylate (21 mg, 51%). Mass spectrum m/z 405.0 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=2.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 7.31 (dd, J=8.4, 2.4 Hz, 1 H), 7.25 (dd, J=5.5, 2.4 Hz, 1 H), 3.65 (s, 3 H), 3.17 (d, J=5.3 Hz, 2 H), 2.45 (m, 1 H), 2.01 (m, 1 H), 1.73 (m, 1 H), 1.66 (s, 3 H), 1.58 (m, 2 H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1>>[CH3:29][C:30]1[N:31]=[C:32]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([O:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:33][CH:34]=1
Reactant: Cc1cscn1
Reactant: C[Si](C)(C)OC1(c2cccc(Cn3nnc4c(Cl)nc(N)nc43)n2)CCCC1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O[Si](C)(C)C)CCCC3)n2)n1
Yield: 20 %

Procedure:
Prepared from 7-chloro-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 4-methylthiazole by the method described for Example 30 to give the title compound (0.105 g, 20%); NMR δH (400 MHz, DMSO) 7.77 (1H, t, J 7.9 Hz), 7.72 (1H, s), 7.44 (1H, d, J 7.9 Hz), 7.35 (2H, br s), 7.14 (1H, d, J 7.4 Hz), 5.82 (2H, s), 2.56 (3H, s), 1.84 (2H, m), 1.73 (2H, m), 1.64 (2H, m), 1.40 (3H, m), −0.10 (9H, s); (M+H)+ 481.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:41][O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH2:55])[CH:52]=[N:51]2)[O:47][CH:48]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:41][O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH:55][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:52]=[N:51]2)[O:47][CH:48]=1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-phenyloxazole-4-carboxylic acid (WO 2009/077990, p. 113) (955 mg, 4.70 mmol) in CH2Cl2 (27 mL) was treated at rt with DMAP (143 mg, 1.17 mmol), HOBt (763 mg, 5.65 mmol), EDC (2.25 g, 11.75 mmol) and DIPEA (3.22 mL, 18.80 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (983 mg, 4.70 mmol) in CH2Cl2 (20 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (40 mL), the layers were separated and the org. phase was washed with water (40 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by crystallization for EA to give the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.14. LC-MS-conditions 07: tR=0.84 min, [M+H]+=395.44.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCCOC1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCCOC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9H-purine-2,6-diamine trifluoroacetate (400 mg) in N,N-dimethylformamide (6.90 ml) at room temperature was added potassium carbonate (610 mg) and the reaction stirred at 60° C. for 90 minutes. The reaction mixture was cooled to room temperature and tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (236 mg) was added. Stirring was continued at 50° C. for 20 hours. The reaction temperature was increased to 90° C. and stirring continued. The reaction was cooled and taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-50%) to afford the title compound as a colourless oil (198 mg, 88% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=4)=[O:24])[NH:12][C@H:11]3[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:5]2=[CH:4][CH:3]=1.CC[N:42]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:31]([C:29]1[N:30]=[C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:34][C:35]([CH3:37])([CH3:38])[CH3:36])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:39])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])[S:27][CH:28]=1)(=[O:33])[NH2:42]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2nc(C(=O)O)cs2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2nc(C(N)=O)cs2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a solution of rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-thiazole-4-carboxylic acid (40 mg, 0.07 mmol) prepared in Example 197 in anhydrous DMF (2 mL) were added EDCI (26 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol), NH4Cl (36 mg, 0.67 mmol), and triethylamine (14 mg, 0.13 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-thiazol-2-yl)-amide as a off white solid (12 mg, 30%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCSc1cccc[n+]1[O-]
Agent: Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCSc2cccc[n+]2[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 4.12 g of 2-β-aminoethylthio pyridine N-oxide hydrochloride in 60 cc of water, there are added 4 cc of 5 N soda, then 3.8 g of p-toluenesulfonyl chloride. The mixture is agitated for 5 hours at ambient temperature. The pH is maintained at 9.5 by the addition of normal soda. The precipitate is filtered and crystallized in aqueous ethanol. Yield=88%. Fusion point: 201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#N.C(O)=[O:12]>[Al].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:12]
Reactant: O=CO
Reactant: Cc1ccc(C#N)cc1Cl
Agent: [Ni]
Agent: [Al]
Product: Cc1ccc(C=O)cc1Cl

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (4.0 g, 26.39 mmol), formic acid (72 ml, 75% v/v) and nickel aluminum alloy (50/50, 4.8 g) was stirred and heated under reflux for 2 h. The reaction mixture was then filtered hot through Hyflo, and the residue was washed well with hot ethanol. The filtrate was concentrated under reduced pressure to yield a sticky solid. Distillation of this solid afforded 3-chloro-4-methylbenzaldehyde as a colourless oil, b.p. 73°-74°/0.8 mmHg.