Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH2:4](I)[CH3:5]>>[CH3:4][CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:2]/[CH:2]=[CH:4]\[CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:4][CH2:5][CH2:1][CH3:2]
Reactant: [Li]CC
Reactant: CCI
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC

Procedure:
Example 8 is repeated, using ethyl-lithium prepared from 156 grams of ethyl iodide.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1.[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[CH2:44][CH2:43][NH:42][C:41]2=[O:45])=[N:37][C:36]=1[CH3:46])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[CH2:44][CH2:43][N:42]([CH2:12][C:13]3[N:17]=[C:16]([CH3:18])[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=3)[C:41]2=[O:45])=[N:37][C:36]=1[CH3:46])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc(CBr)nn1-c1ccccc1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3nc(C)n(-c4ccccc4)n3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 3-(bromomethyl)-5-methyl-1-phenyl-1H-1,2,4-triazole to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 17% yield: mp 139-141° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.3 Hz, 2H), 7.49-7.29 (m, 8H), 5.88 (s, 1H), 4.62 (s, 2H), 4.57 (d, J=5.6 Hz, 2H), 4.13-4.08 (m, 2H), 3.68-3.62 (m, 2H), 2.63 (s, 3H), 2.41 (s, 3H); MS (ES+) m/z 488.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Br)c2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Br)cccc2-3)no1
Yield: 68 %

Procedure:
2.04 g (5 mmol) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one were stirred at room temperature for 4 hours with 1.5 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.61 g (68%) of 7-bromo-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 135°-145°.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13](=[O:33])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1>CCCCC.O1CCCC1>[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[CH2:41][N:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=2)[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:13]1=[O:33]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (55.9 mg 1.397 mmol; 60% dispersion in mineral oil) is washed with pentane (2×10 ml) and suspended in tetrahydrofuran (10 ml). A solution of ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 4A) (500 mg, 1.164 mmol) in tetrahydrofuran (5 ml) is added with stirring. After 5 minutes at room temperature, a solution of 1-bromo-3-(bromomethyl)benzene (320 mg, 1.23 mmol) in tetrahydrofuran (5 ml) is added, and the reaction is stirred at room temperature for 16 h. The solution is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The yellow residue (approximately 1.05 g) is purified by flash chromatography over silica gel 60 (50 g) with cyclohexane/ethyl acetate (5:1) as eluent. The product is isolated as an amorphous foam.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[N:17][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15]2)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[N:17][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2nn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2nn1
Reaction time: 24 h

Procedure:
Palladium on charcoal catalyst (30% w/w; 100 mg.) was added to a solution of ethyl 6-(benzyloxycarbonylamino)-cinnolin-3-yl carboxylate (1 g.) in dry ethanol (25 ml.). The solution was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 24 hours. The mixture was filtered and the filtrate evaporated in vacuo to give, as solid residue, ethyl 6-aminocinnolin-3-yl carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[N:41][CH:42]=1>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)=[N:41][CH:42]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Product: COc1ccc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)nc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C[C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[B].N>O.CO>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][O:9][CH3:7])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [B]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of carbon tetrachloride were added 2.72 g of 7-ACA, 4.3 g of a boron trifluoridediethylether complex, and 3.5 g of methanol. The mixture was heated at 60° C. for 35 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 20 ml of cold water. Then, the mixture was adjusted to pH 7.5 with 28% aqueous ammonia at a temperature of 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was applied to the same column as used in Example 2. The elution was conducted using water as an eluent. The resulting eluate was adjusted to pH 3.5 with 36% hydrochloric acid to hereby form a precipitate. The precipitate was collected by filtration, and washed with 5 ml of cold water and, then, with 5 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.27 g. The yield of the desired product was as low as 11.1%.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:35](=[O:36])[CH2:34][Cl:33])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCl)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.84 g) in dimethylformamide (100 ml), chloroacetyl chloride (8.48 g) is added, and the resultant mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaked with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to remove the solvent, and the residue is washed with ether to give 2-carbobenzoxyaminomethyl-3-(2-chloroacetamido)-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.9 g). This product is recrystallized from ethyl acetate to give crystals melting at 130° to 134° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][C:13](O)=[O:14])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[OH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(N1C=CN=C1)(N1C=CN=C1)=O>>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][C:13]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[OH:20])=[O:14])=[CH:4][C:3]=1[C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)c1cc(CC(=O)Nc2ccccc2O)cc(C(C)(C)C)c1O
Yield: 86.2 %

Procedure:
Using previously described procedures with 4-hydroxy-3,5-di-t-butyl-phenylacetic acid (45 g, 0.17 mol), 2-hydroxyaniline (20.7 g, 0.19 mol) and 1,1′-carbonyl diimidazole (29 g, 0.18 mol) the title compound (52.1 g, 86%) was obtained as a tan solid.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]>CN(C)C=O>[Si:6]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1OCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Imidazole (241 mg, 3.54 mmol, 2.2 equiv) and tert-butyl-dimethylsilyl chloride (267 mg, 1.77 mmol, 1.1 equiv) are added to a solution of (3S)-dihydro-3-hydroxy-2(3H)-furanone 11 (164 mg, 1.61 mmol) in dimethyl formamide (1.5 ml). The mixture is stirred for 24 h at r.t. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 10:1) affords (S)-2-(tert-butyidimethylsilyloxy)-γ-butyrolactone 12 (321 mg, 93%) as a colourless oil. [α]D20=−31.7; [α]54620=−37.4 (c=0.86, CHCl3); 13C-NMR (100 MHz, CDCL3): δ(ppm)=175.8; 68.2; 64.7; 32.3; 25.6; 18.2; −4.8; −5.3
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3OC)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1-c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 7-hydroxy-2-(2-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (120 mg, 0.36 mmole) and glycine (546 mg, 7.27 mmole) in 0.5 M sodium methoxide/methanol (13.8 ml, 6.91 mmole) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 ml) and extracted with methyl tert-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The resulting jelly was extracted with dichloromethane and ethyl acetate. The organic layer was combined, washed with brine and dried in vacuo to give the title compound as a yellow solid (94 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.39 (br s, 1H), 8.88 (s, 1H), 8.45 (d, 1H), 7.62 (m, 1H), 7.33 (d, 1H), 7.18 (t, 1H), 4.01 (s, 3H), 4.03 (d, 2H); MS: (+) m/z 360.25 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1.CN(C)C=O>C(O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A stirred solution of 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (50 mg, 0.194 mmol), 5-fluoro-1,3-dihydro-indol-2-one (28 mg, 0.184 mmol), piperidine (0.05 ml), N,N-dimethylformamide (0.05 ml) in anhydrous ethanol (0.5 ml) was heated to reflux for 2 hours and stirred at room temperature overnight. The resulting mixture was filtered to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 65.92%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:18]#N)=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23].[NH4+].[OH-:25]>OS(O)(=O)=O.O>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:18]([O:23][CH3:22])=[O:25])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccccc1
Reactant: [OH-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: CCc1nc2c(C)cc(C(=O)OC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 440 mg(1.59 mmol) of the product of Step E in H2SO4 (4 mL) and H2O (4 mL) was heated to 80° C. for 8 hours. The reaction was cooled, MeOH (150 mL) was added, then conc NH4OH was added until the mixture turned basic. The white solid (NH4)2SO4 was filtered and washed with MeOH. The water and MeOH were removed in vacuo and and the residue was taken up in MeOH and then filtered to remove any remaining (NH4)2SO4. After concentrating, and removal of water from the residue by evaporation from toluene, anhydrous 3% HCl-MeOH (50 mL) was added and the mixture was stirred overnight at rt. Filtration, concentration, and extraction from 5% aqueous Na2CO3 with CH2Cl2 gave 750 mg of the crude title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](OC)([O:24]C)[CH3:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(OCC)(=O)C>[C:22]([C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:17][CH:18]=1)(=[O:24])[CH3:23]
Reactant: COC(C)(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 60 °C
Yield: 96.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-propionamide (1.22 g, 2.459 mmol) in acetone (28 mL) and water (3 mL) was treated with p-toluenesulfonic acid monohydrate (142.5 mg, 0.738 mmol). The reaction mixture was heated to 60° C. for 30 min and then was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/3 ethyl acetate/hexanes) afforded the N-(5-acetyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide as a white foam (1.07 g, 96%): mp 77–80° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H24ClN3O4S (M+H)+ 450.1249, found 450.1253.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][CH2:12][CH:13]([OH:17])[C:14]([OH:16])=[O:15])[C:9]=2[N:10]=1.Cl.[CH2:20](O)[CH3:21]>>[CH2:20]([O:15][C:14](=[O:16])[CH:13]([OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:18])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2)[CH3:21]
Reactant: CCO
Reactant: Nc1nc2c(ncn2CCC(O)C(=O)O)c(=O)[nH]1
Agent: Cl
Product: CCOC(=O)C(O)CCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-Amino-1,6-dihydro-6-oxopurin-9-yl)-2-hydroxybutyric acid (2.00 g, 7.9 mmole; prepared according to Example 3) was mixed with 500 ml of ethanol. The mixture was saturated with hydrogen chloride gas, first without cooling and then with cooling in ice-water. The total addition time was about 15 minutes. The mixture was then slowly warmed to room temperature and allowed to stand over night. After evaporation of the solvent, the residue was treated three times each with 25 ml of ethanol, the solvent being reevaporated after each treatment. The residue was then dissolved in 12 ml of water and the pH adjusted to 6-7 with saturated aqueous sodium bicarbonate. The precipitate was filtered off, washed with 2 ml of water and dried in vacuo to yield 1.60 g. Recrystallization from ethanol gave a pure product, m.p. 161°-3° C. (a sample for analysis had m.p. 162°-3° C.). Analyses--Found: C 46.96; H 5.35; N 24.77; O 22.60%. Calculated for C11H15N5O4 : C 46.97; H 5.38; N 24.90; O 22.75%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=1.B(Br)(Br)Br>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1
Reactant: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To an ice-cooled solution of 5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)-pyrazole (3.0 g, 10.0 mmol) in methylene chloride (25 ml) was added boron tribromide (51 ml, 51 mmol, 1 M solution in methylene chloride). After 1 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (2.4 g).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=1[CH2:13][SH:14].[OH-:20].[Na+].O>CN(C=O)C>[CH3:10][C:11]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=1[CH2:13][S:14][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-:20]
Reactant: Cc1ccnc(Br)c1
Reactant: [OH-]
Reactant: Cc1ccc(C)c(CS)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)c(CSc2cc(C)cc[n+]2[O-])c1

Procedure:
A mixture of 1.34 g (0.006 mole) of 2-bromo-4-methylpyridine hydrochloride, 1.06 g (0.007 mole) of 2,5-dimethylbenzylmercaptan and 0.56 g (0.014 mole) of powdered sodium hydroxide were stirred together at room temperature in 15 ml of DMF for 15 minutes. The reaction mixture was poured into water and the precipitate filtered off and washed with water. Yield 1.47 g or 95%.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl.[N:11](OS(=O)(=O)O)=O.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[OH-].[Na+]>O.CO>[OH:25][C:20]1[CH:21]=[CH:22][C:23]([N:11]=[N:7][C:6]2[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:24][C:19]=1[Br:18]
Reactant: O=NOS(=O)(=O)O
Reactant: N#Cc1ccc(N)cc1
Reactant: Oc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N=Nc2ccc(O)c(Br)c2)cc1
Reaction time: 1 h

Procedure:
18.8 g 4-cyanoaniline are heated at 60° C. in 100 ml water. To dissolve the solid, 10 ml conc. hydrochloric acid are added. A further 115 ml hydrochloric acid are then added, the temperature of the solution is brought to 0° C., 52 g nitrosylsulfuric acid are slowly added dropwise and the mixture is stirred for 1 h. This solution is slowly added dropwise to a solution of 27.5 g 2-bromophenol, 100 ml methanol and 100 ml water at 10° C. A pH of 6–6.5 is maintained by simultaneous addition of 10% sodium hydroxide solution. When the addition is complete, the stirred mass is allowed to react for a further hour and the precipitate is filtered off with suction. The product is then washed with water and dried. The yield of 4-hydroxy-3-bromo-4′-cyanoazobenzene is 68 g.
Reaction SMILES: C(OC(=O)[N:7]([CH:27]([CH3:29])[CH3:28])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(O)CCC>[CH:27]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:28])[CH3:29]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1nccn2c(-c3ccnc(S(C)(=O)=O)n3)cnc12
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCCCO
Product: CC(C)Nc1nccn2c(-c3ccnc(Nc4ccccc4)n3)cnc12

Procedure:
To isopropyl-[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (117 mg, 0.27 mmol) (from Example 11 supra) was added aniline (38 μL, 0.42 mmol) in nBuOH (3 mL) followed by conc.HCl (38 μL, 0.46 mmol) and the reaction was shaken at 95° C. overnight. After this time the reaction was concentrated to dryness, dissolved in DMSO (1.8 mL) and then purified by preparative HPLC to give isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine. (Yield 27.3 mg, 29%). LC-MS: [M+H]+ 346.3.