Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)N4CCOCC4)s3)n2)n1
Reaction time: 2 h
Yield: 71 %

Procedure:
To 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid (prepared in an analogous manner to Intermediate 62, 24 mg, 61 μmol) in anhydrous DMF (0.5 mL) was added (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (17 mg, 73 μmol), HOAt (4.1 mg, 31 μmol) and morpholine (10 μL, 92 μmol). The reaction mixture was stirred for 2 h, further morpholine (10 μL, 92 μmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (9 mg, 39 μmol) were added. The mixture was stirred for a further 2 h then diluted with ethyl acetate (5 mL) and extracted with aqueous citric acid (1M, 5 mL), 1 M NaOH (5 mL), saturated brine (5 mL) and dried over sodium sulphate. Removal of the solvent gave a gum with was purified on silica eluting with ethyl acetate-10% heptanes to give the title compound (20 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(NCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C1CCC(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-benzylamino-cyclohexanecarboxylic acid tert-butyl ester (630 mg, 2.180 mmol) in DMF (20 mL) is added t-butyl bromoacetate (1 mL, 6.856 mmol) and Cs2CO3 (1.0 g, 3.069 mmol). The mixture stirs for 2 h. Then H2O (50 mL) is added the mixture is extracted with EtOAc (2×100 mL), dried with sodium sulfate and concentrated. The resulting solid is purified by flash chromatography (gradient elution: 0-20% EtOAc/Hep) which affords 300 mg of 4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 5H), 1.38 (m, 18H), 1.86 (m, 4H), 2.09 (m, 1H), 3.14 (m, 2H), 3.71 (m, 2H), 7.29 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].C(Cl)[Cl:22]>O1CCOCC1>[ClH:22].[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)C(F)(F)F)C1
Reactant: ClCCl
Solvent: C1COCCO1
Product: Cl
Product: O=C(NC[C@@H]1CCNC1)C(F)(F)F

Procedure:
To a 100 mL round-bottomed flask was added 1,1-dimethylethyl (3S)-3-{[(trifluoroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (830 mg, 2.80 mmol) in DCM (25 ml) at 25° C. to give a colorless solution. 4N HCl (3.50 ml, 14.01 mmol) in dioxane was added and the reaction was allowed to stir o/n. The reaction was concentrated under vacuum to give the desired compound as colorless oil which was used in the next reaction without further purification. Isolated 2,2,2-trifluoro-N-[(3R)-3-pyrrolidinylmethyl]acetamide (550 mg, 2.364 mmol, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cccc(C=O)n1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)n1
Yield: 15.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 6-Methoxy-pyridine-2-carbaldehyde (25.7 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 11.03 mg (19%) of the title compound. (300 MHz, DMSO-d6) 13.30 (s, 1H), 8.01 (s, 1H), 7.89 (t, J=15 Hz, 7.5 Hz, 1H), 7.79 (m, 2H), 7.30 (d, J=9 Hz, 1H), 7.25 (s, 1H), 6.90 (d, J=8 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 5.17 (t, J=17 Hz, J=9 Hz, 1H), 4.06 (s, 3H), 2.90 (s, 1H), 2.82 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=411 (M+H), HPLC: 2.53 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]2[O:10][CH2:11][O:12][C:5]2=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([CH2:21][CH:22]=1)=[CH:19][CH:18]=[C:17]([N:23]([CH3:25])[CH3:24])[CH:16]=2.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.CCCCCC.CCOC(C)=O>[C:26]([NH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]2[O:10][CH2:11][O:12][C:5]2=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([CH2:21][CH:22]=1)=[CH:19][CH:18]=[C:17]([N:23]([CH3:25])[CH3:24])[CH:16]=2)(=[O:28])[CH3:27]
Reactant: CN(C)c1ccc2c(c1)OC(c1cc3c(c(C#N)c1N)OCO3)=CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=O)Nc1c(C2=CCc3ccc(N(C)C)cc3O2)cc2c(c1C#N)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.2 %

Procedure:
To a solution of 2-amino-3-cyano-7-dimethylamino-4-(methylenedioxy)phenyl-4H-chromene (43 mg, 0.13 mmol) in pyridine (1 ml) was added acetic anhydride (0.25 ml, 2.6 mmol) at room temperature. The mixture was stirred at room temperature for 3 days, then diluted with 1:1 hexane/EtOAc (40 ml), washed with water, 2N HCl, water, 2N NaOH, water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (3:2 hexane/EtOAc) to yield the title compound as a yellow solid (4 mg, 8%). 1H NMR (CDCl3): 6.84-6.73 (m, 4H), 6.50-6.46 (m, 1H), 6.31 (m, 1H), 5.95, 5.94 (2s, 2H), 4.79 (s, 1H), 2.94 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:32])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[O:18])=[C:11]([F:33])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 70 °C
Yield: 87.6 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 0.214 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.098 g, 0.278 mmol) and K2CO3 (0.089 g, 0.642 mmol) in dioxane (2 mL) and H2O (0.333 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.012 g, 10.70 μmol), sparged with Ar again, and heated to 70° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (124 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H); 8.58-8.59 (m, 2H); 8.39 (d, J=5.7 Hz, 1H); 8.23 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 8.01 (s, 1H); 7.60-7.62 (m, 3H); 7.43 (m, 2H); 7.19 (d, J=2.5 Hz, 1H); 6.43-6.75 (m, 2H); 4.18 (t, J=5.1 Hz, 2H); 3.89 (t, J=5.2 Hz, 2H); 0.75 (s, 9H); −0.12 (s, 6H); MS (ESI) m/z: 662.3 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH2:27][O:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:31][CH:30]=1)([CH3:26])[CH2:18][CH2:17]2)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:10]([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH2:27][O:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][CH:34]3[S:38][C:37](=[O:39])[N:36]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:35]3=[O:40])=[CH:31][CH:30]=1)([CH3:26])[CH2:18][CH2:17]2)(=[O:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.87 g of t-butyl bromoacetate was added dropwise, whilst ice-cooling, to a mixture of 1 g of 5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl ]thiazolidine-2,4-dione [prepared as described in Example 3(b) of copending U.S. Ser. No. 644,996], 0.43 g of anhydrous potassium carbonate, and 8 ml of acetone. The resulting mixture was stirred for 2 hours at room temperature and then allowed to stand for 2 days, also at room temperature. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent:benzene) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:28][O:27][C:22]1[C:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:5]=[C:6]([N:8]([CH3:15])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[N:20]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3cccnc3O)n2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ncccc1-c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To 3-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridin-2-ol (Intermediate 63, 0.31 mmol) was added DMF (2 mL), potassium carbonate (85 mg, 0.52 mmol) and methyl iodide (19 μL, 0.31 mmol). The resulting mixture was stirred for 2 h, after which time further methyl iodide (40 μL, 0.62 mmol) was added. The reaction was stirred for a further 1.5 h after which time further methyl iodide (60 μL, 0.93 mmol) was added. This sequence was repeated two more times after which the starting material had been consumed. The crude mixture was diluted with ethyl acetate (10 mL), extracted with water (5 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by chromatography on silica eluting with a gradient of 2% to 6% MeOH-DCM and then by trituration with hot methanol (2 mL) to give the title compound (44 mg, 38%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:38])[CH:30]=3)[CH2:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:26]3[CH2:25][C:24]([C:19]4[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[CH:18]=4)([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=3)=[CH:30][C:31]=2[CH3:38])=[N:3][CH:4]=1)#[N:9]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a solution of 0.39 g of 2-amino-5-cyanopyridine and 0.71 g of pyridine in 20 mL of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 20 mL of dichloromethane was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 1.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>C(O)(=O)CC>[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(O)ccnc2c1
Solvent: CCC(=O)O
Product: Cc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (6 mL of 70%) was slowly added to a hot (125° C.) solution of 7-methyl-4-quinolinol (10.5 g) in propionic acid (125 mL). The reaction mixture was stirred for about 1.5 hours and then it was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed well with ethanol and water and then dried to provide 6.9 g of 7-methyl-3-nitro-4-quinolinol as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][C:42](Cl)=[CH:41][C:37]=2[CH:38]=[N:39][CH:40]=1)=[O:34])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([O:32][C:33]([C:35]1[C:36]2[S:43][CH:42]=[CH:41][C:37]=2[C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1)=[O:34])[CH3:31]
Reactant: CCOC(=O)c1cncc2cc(Cl)sc12
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c2ccsc12
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To the solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL N,N-dimethylformamide, 27 mg (0.61 mmol) sodium hydride was added. After 15 min. 148 mg (0.61 mmol) chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was added and stirring was continued for another 2 h at room temperature. The reaction was poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate. The phases were separated, the aqueous layers extracted with 20 mL ethyl acetate and the combined organic layers washed with 20 mL water and 20 mL brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 75:25) to give the desired compound as a white solid (71%). MS (Turbo Spray): m/z=596.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[O:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCC(C)(CC)c1cc(N)on1
Solvent: Cc1ccccc1
Product: CCC(C)(CC)c1cc(NC(=O)c2c(OC)cccc2OC)on1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred solution of 3.36 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole in 65 liters of toluene was added portion-wise over thirty minutes 4.015 Kg of 2,6-dimethoxybenzoyl chloride. The reaction mixture was heated to reflux and stirred for forty-eight hours. It was then cooled to room temperature and concentrated to a volume of about 25 liters by evaporation of the solvent under reduced pressure. The product precipitated and was collected by filtration, washed with fresh toluene, and air dried to provide 6.084 Kg of N-[3-(1-ethyl-1-methylpropyl]-5-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 172°-174° C. Yield 91%.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH2:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Clc1nccs1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
Toluene (60 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-chlorothiazole (2.00 g, 16.73 mmol) and tert-butyl acetate (2.137 g, 18.40 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 61.3 mL, 36.8 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h. The orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography on silica (0-25% ethyl acetate in hexanes) afforded tert-butyl (1,3-thiazol-2-yl)acetate (770 mg, 23%) as a pale yellow oil. MS ESI: [M t-Bu]+ m/z 144.0.
Reaction SMILES: [NH2:1][C:2](=[S:14])[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>C(Cl)Cl>[C:9]([O:8][C:7](=[O:13])[NH:6][C:3]([CH3:5])([CH3:4])[C:2]([N:1]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[S:14])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reactant: COC(C)(OC)N(C)C
Solvent: ClCCl
Product: CC(=NC(=S)C(C)(C)NC(=O)OC(C)(C)C)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 1-amino-2-methyl-1-thioxopropan-2-ylcarbamate (Example 12 b, 0.218 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (CAN 18871-66-4, 0.16 g, 1.2 mmol) in methylene chloride (10 mL) was stirred at room temperature for 24 h. Then it was concentrated to give crude product, which was used directly in the next step without further purification (0.28 g, 98%) as yellow oil; MS (EI): m/e 288.2 [M+H]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.Cl.[C:7]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12])#[N:8]>>[C:7]([C:9]1[CH:10]=[C:11]([NH:12][NH2:1])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])#[N:8]
Reactant: COc1ccc(N)cc1C#N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(NN)cc1C#N
Yield: 69.1 %

Procedure:
To an aqueous solution (150 ml) of 3-cyano-4-methoxyaniline hydrochloride (72 g) were added sodium nitrite (29.7 g), stannous chloride dihydrate (266 g) and con. hydrochloric acid (437 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration. The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 44 g of 3-cyano-4-methoxyphenylhydrazine.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nn(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nn(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate (1.38 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile (0.72 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.45 g, 55%).