Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 75 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 1.5 g (4.20 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 4.20 mmol) were used to afford 1.7 g of the required product. Percentage purity (LCMS): 74.6%, (M+1)=539.2 (with BOC).
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A solution of isoamyl nitrite (4.02 mL, 30 mmol) in dimethyl disulfide (19.8 mL, 220 mmol) at 25° C. was slowly treated with 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80–90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.73 g, 87%) as a brown oil: EI-HRMS m/e calcd for C8H6BrF3S (M+) 269.9326, found 269.9327.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([CH2:23][CH2:24][OH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1.C1(C=C)C=CC=CC=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OCCc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C=Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-phenylethanol and DBU in DME. EI-MS m/e (%): 316 (M+, 4), 212 ([M—PhCH═CH2]+, 100), 184 (28), 170 (20), 104 ([PhCH═CH2]+, 84), 77 (20).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 52(c), but using 139 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxamide [prepared as described in step (g) above], 96 mg of the hydrochloride of the title compound were obtained as a powder, melting at above 160° C. (with softening).
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@:41]([CH3:47])([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:47][C@@:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:45][CH3:46])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)N[C@H](CC(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 97.8 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (R)-2-(tert-butoxycarbonylamino)-2-methylbutanoic acid (320 mg) were used, whereby tert-butyl (2R)-2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxobutan-2-ylcarbamate (844 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (528 mg) was yielded.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH:9]=C)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.C(Cl)Cl.[O:22]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[CH3:1][CH:2]([CH2:8][CH:9]=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1COCCO1
Reactant: C=CCC(C)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C(C)CC=O
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
A colorless solution of ethyl 2-methylpent-4-enoate (5.000 g; 35.16 mmol) in dioxane (260 ml) and water (85 ml) was treated successively with 2,6-lutidine (7.536 g; 70.32 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.45 ml), and NaIO4 (30.083 g; 140.65 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 20.5 h. The resulting milky mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude ethyl 2-methyl-4-oxobutanoate as a dark-yellow/slightly brown oil which was directly used for the next step without additional purification.
Reaction SMILES: [CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:29][C:27]3[CH:26]=[CH:25][C:23]4[N:24]=[C:20]([N:19]([CH2:18][CH2:17][N:16]([CH3:15])[CH3:31])[CH3:30])[S:21][C:22]=4[CH:28]=3)=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C2CCCC2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4CCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclopentyl-benzoic acid (0.099 g, 0.52 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.10 g, 0.40 mmol) to give 0.38 g (23%) of product. LC/MS: Retention time=4.97 min; (m/z): calcd for C24H30N4OS (M+H)+: 423.6; found: 423.0.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(NC2CCC(F)(F)CC2)CCCCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:24]1([N:15]([CH:16]2[CH2:17][CH2:18][C:19]([F:22])([F:23])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(F)(F)CC2)s1
Agent: CCOC(=O)CS
Agent: FC1(F)CCC(NC2CCCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(F)(F)CC2)s1

Procedure:
{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared using general procedures (A) and (B) using cyclohexyl-(4,4-difluoro-cyclohexyl)-amine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][N:12](CC4C=CC=CC=4)[CH2:11]3)=[N:9][C:5]=2[CH:4]=1.Cl.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C3CNCCO3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a solution of 5-(methyloxy)-2-[4-(phenylmethyl)-2-morpholinyl]-1H-benzimidazole (2.0 g, 6.18 mmol), and hydrogen chloride (0.451 g, 12.37 mmol) in CH3OH (50 mL) stirred under nitrogen at room temperature was added palladium on carbon (0.066 g, 0.618 mmol). The reaction mixture was stirred under hydrogen at 25° C. for 3 hours. CH2Cl2 was added and the mixture was filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with 90:10 CH2Cl2/CH3OH to afford the title compound (500 mg). LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=2[F:26])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (32 mg, 18%), MS (ISP) m/z=365.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (157 mg, 0.5 mmol) and commercially available 2,3,4-trifluorophenylboronic acid (114 mg, 0.65 mmol).
Reaction SMILES: C(OC(=O)[C@H](CCCCNC(OCC1C=CC=CC=1)=O)N)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C[O:42][C:43]([CH2:45][CH2:46][CH:47]([CH3:60])[C:48]([NH:50][C@H:51]([C:57]([OH:59])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])=[O:44].N[C@H](C(O)=O)CCCCN>>[C:43]([CH2:45][CH2:46][CH:47]([CH3:60])[C:48]([NH:50][C@H:51]([C:57]([OH:59])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])([OH:44])=[O:42]
Reactant: COC(=O)CCC(C)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Product: CC(CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
By substituting Nε -benzyloxycarbonyl-L-lysine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23 and then treating the product by the procedures of Examples 24 and 26, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-N68 -benzyloxycarbonyl-L-lysine benzyl ester, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-L-lysine and Nα -(4-carboxy)-2-methylbutanoyl)-L-lysine are obtained.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=3)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:37]([F:40])([F:39])[F:38])[C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=4)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]3)=[N:4][CH:3]=2)=[CH:31][C:32]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CS(=O)(=O)NCc1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)NCc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 105 °C
Yield: 6 %

Procedure:
N-[3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl) -benzyl]-methanesulfonamide (77 mg, 0.177 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (76 mg, 0.265 mmol, 1.5 eq), K2CO3 (73 mg, 0.531 mmol, 3 eq), H2O (2 mL) and dichlorobis(triphenylphosphine)palladium(II)(12 mg, 0.0177 mmol, 0.1 eq) were added. The reaction mixture was heated in a pressure tube at 105° C. overnight. Solvents were removed and the residue obtained was suspended in water and extracted twice with EtOAc. The organic layers were dried, filtered end evaporated. The residue was triturated with CH3CN and filtered. The solid was purified in an Isolute Si II cartridge (DCM/MeOH, 0%-5%). The product obtained was precipitated in CH3CN and filtered to give the desired product (5 mg, 6%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.70 min, [M+H]+ m/z 469.1; 1H NMR (300 MHz, DMSO) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.80 (s, 1H), 7.73 (t, J=6.3 Hz, 1H), 7.62 (d, J=4.7 Hz, 2H), 6.74 (s, 2H), 4.29 (d, J=6.3 Hz, 2H), 2.93 (s, 3H).
Reaction SMILES: ON1C(=O)CCC1=O.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22]([C:29]1[C:30](=[O:37])[NH:31][NH:32][C:33]=1[CH:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([C:29]1[C:30](=[O:37])[NH:31][N:32]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:33]=1[CH:34]([CH3:35])[CH3:36])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Hydroxysuccinimide (1.06 g) was dissolved in tetrahydrofuran (10 g) at room temperature. Triethylamine (0.936 g) and ethyl chloroformate (1.00 g) were added to the solution successively. After stirring the reaction mixture at room temperature for 30 minutes, 4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was added to the mixture at room temperature. After the reaction mixture was stirred at room temperature for 13 hours, the reaction mixture was stirred at 50° C. for 6 hours. The insoluble materials were removed, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.CI.[C:27](OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(C)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH3:27])[N:13]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CI
Product: Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.028 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using methyl iodide (0.21 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-methyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C14H16ClN3, 261.10; found, m/z 262.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69-7.65 (m, 4H), 4.07 (s, 3H), 3.69-3.67 (m, 2H), 3.58-3.56 (m, 2H), 3.44-3.42 (m, 2H), 3.05-3.04 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21](=O)[CH:22]([CH3:24])[CH3:23]>C(O)C>[CH:22]([C:21]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[CH:20]=1)([CH3:24])[CH3:23]
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Reactant: CC(C)C(=O)CBr
Solvent: CCO
Product: CC(C)c1cn2cccc(OCC3(c4ccccc4)CC3)c2n1
Yield: 75.9 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.84 g, 3.50 mmol, see example 23), 1-bromo-3-methyl-2-butanone (0.69 g, 4.2 mmol) and molecular sieves (4.2 g, type 4 Å, beads, 8–12 mesh) in anhydrous ethanol (10 mL) was refluxed for 24 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (20 mL) and then extracted with ethyl acetate (3×40 mL). The organic extracts were combined, washed with water (2×5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 0.814 g (76% yield) of 2-isopropyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine as a free base (Rf=0.60 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.755 g, 2.46 mmol) in anhydrous diethyl ether (10 mL) was treated with ethereal hydrogen chloride (50 mL) to form the hydrochloride salt. After 1 h, the solvent was decanted and the title compound was isolated as a solid (0.844 g, quantitative). 1H-NMR (300 MHz, CDCl3) δ 15.59 (br s, 1H, +NH), 8.36 (m, 1H, Ar), 7.85 (d, 1H, Ar), 7.63 (d, 2H, Ar), 7.24 (m, 2H, Ar), 7.13 (m, 1H, Ar), 7.01 (t, 1H, Ar), 6.74 (d, 1H, Ar), 4.29 (s, 2H, CH20), 3.64 (m, 1H, CH), 1.40 (d, 6H, 2CH3), 1.12 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 145.64 (+), 144.89 (+), 142.33 (+), 133.36 (+), 130.04 (−), 128.27 (−), 126.78 (−), 120.09 (−), 116.68 (−), 110.31 (−), 109.82 (−), 77.99 (+), 25.51 (−), 25.45 (+), 21.99 (−), 11.45 (+); LRMS-ES m/z: MH+ 307.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH:28]=1.C([O-])(O)=O.[Na+]>ClCCl>[O:27]1[C:23]2[CH:22]=[CH:21][C:20]([NH:19][S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])=[CH:28][C:24]=2[CH:25]=[N:26]1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2oncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2oncc2c1)c1cc(Cl)ccc1Cl
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (192 mg, 0.783 mmol), in dichloromethane (4 mL) was added pyridine (150 μL, 1.86 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-1,2-benzisoxazole (100 mg, 0.746 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (174 mg, 68%), single spot at Rf 0.68 (1:1 hexane:ethyl acetate). mp 172.9-173.6° C., HPLC purity 99+% (tR 2.41 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.64 (1H, s), 7.89 (1H, d, J=2.2 Hz), 7.56-7.28 (5H, m). LCMS: 341.07 (M−). FAB-MS (MH+, C13H8Cl2N2O3S): calcd 342.9711, found 342.9710.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>CO>[CH:11](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-indanone (5.0 g) and benzaldehyde (4.1 g) in methanol (40 ml), was added 2.2 ml of 48% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 0.5 hr. The resulting precipitate was filtered and washed with water. The yield was 7.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][C:18]3[NH:19][CH:20]=[N:21][CH:22]=3)[C:12]([Br:23])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO>[Br:23][C:12]1[C:13]([NH:15][CH2:16][CH2:17][C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[N:14][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=2)=[N:10][CH:11]=1
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Reactant: CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.6 %

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (1 g, 2.6 mmole, prepared according to procedure 21) was dissolved in MeOH (10 ml), butanal (2.6 ml, 2.9 mmole) was added at room temperature and the reaction mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (266 mg, 3.6 mmole) was added and the reaction mixture was stirred at room temperature overnight. After extraction with ethylacetate/bicarbonate solution (3×) the combined organic layers were washed with saturated NaCl-solution, dried over magnesium sulfate and evaporated. The crude product was purified by flashmaster chromatography (dichloromethane:MeOH 95:5) to provide 5-Bromo-N2-(4-butylamino-phenyl)-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (130 mg). ESI-MS: 431.