Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[NH:12][C:11](=[O:22])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:47]([O:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:21])[NH:55][O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:17]=2)[NH:12][C:11](=[O:22])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOCc1ccccc1)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To an ice-cooled solution of 1-Benzyloxy-7-carboxyquinoxaline-2,3(1H,4H)-dione (422 mg, 1.35 mmol) in 10 ml of N,N-dimethylformamide was added 1-hydroxybenzotriazole (218 mg, 1.48 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol). Stirring was continued for 30 min at 0° C. and O-benzylhydroxylamine hydrochloride (237 mg, 1.49 mmol) and dry triethylamine (0.21 ml, 1.5 mmol) was added. The mixture was stirred overnight at room temperature, then cooled and filtered. The isolated solid was successively washed with water, saturated aqueous sodium hydrogen carbonate and water. Recrystallisation from ethanol gave 290 mg (51%) of the title compound. 1H-NMR (DMSO-d6): 4.95 (s, 2H, CH2), 5.19 (s, 2H, CH2), 7.2-7.8 (m, 13H, ArH), 11.8 (br.s, 1H, exchangeable), 12.3 (br.s, 1H, exchangeable).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:25][N:26]([CH3:31])[S:27]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:4]2[S:5][C:6]([C:7](=[O:8])[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=3)=[C:2]([NH2:1])[N:3]=2)[CH2:20][CH2:21]1)(=[O:29])=[O:28]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2sc(NC3CCN(S(=O)(=O)N(C)C)CC3)nc2N)cc1F
Yield: 22 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone (0.08 g, 0.022 mmol) (Example 7)) was treated with dimethylsulfamoyl chloride in a manner similar to Example 9 except that diisopropylethylamine was additionally used as a catalyst and short plug of silica gel (ethyl acetate was used to pre-purify the sample to give 30 mg (22% yield) of 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid dimethylamide. 1H NMR (DMSO−d6, 300 MHz) δ1.51 (m, 2H, CH2), 1.97 (m, 2H, CH2), 2.77 (s, 6H, 2× NCH2), 2.99 (m, 2H, CH2), 3.52 (m, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 3.89 (s, 3H, OCH3), 7.9-8.5 (brd, 2H, 2NH), 8.71 (brd, 1H, NH). HRMS: (M+H)+: observed: 458.1331; calcd for 4581327.
Reaction SMILES: C(O)C.C([O:6][C:7]([C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11][C:10]=1[CH3:21])=[O:8])C.[OH-].[Na+]>C(O)(=O)C>[CH3:21][C:10]1[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:13][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)c1sc(Nc2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(Nc2ccccc2)sc1C(=O)O
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.9 %

Procedure:
To 70 ml of ethanol, 10.7 g (70 mmol) of phenylthiourea and 11.6 g (70 mmol) of ethyl 2-chloro-3-oxobutanate were dissolved, followed by heating under refluxing for 8 hours. The reaction liquid was concentrated and dissolved in ethyl acetate and the organic layer was washed with an aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. Solid obtained was washed with diisopropyl ether to obtain 16.8 g (yield: 91%) of ethyl 4-methyl-2-(N-phenylamino)thiazole-5-carboxylate. (2) To 50 ml of ethanol, 12.8 g (49 mmol) of ethyl-4-methyl-2-(N-phenylamino)thiazole-5-carboxylate was dissolved, followed by adding 24 g (150 mmol) of 25% sodium hydroxide aqueous solution, and stirring at 80° C. for 15 hours. The reaction liquid was poured into ice water, and acetic acid was added to make acidic. Crystal precipitated was filtered, washed with water and a mixed solvent of hexane/ethyl acetate and dried to obtain 5.50 g (yield: 48%) of 4-methyl-2-(N-phenylamino)thiazole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][C@@H:39]1[NH:44][CH2:43][CH2:42][N:41]([S:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([N:44]2[CH2:43][CH2:42][N:41]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)(=[O:46])=[O:47])[CH2:40][C@@H:39]2[CH3:38])=[O:13])[CH:7]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cnn2cc(Br)cnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(Br)cnc12
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
To a solution of 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (may be prepared as described in Description 17) (471 mg, 1.946 mmol) in N,N-Dimethylformamide (10 mL) under a flush of argon was added HATU (740 mg, 1.946 mmol) and the reaction stirred for 10 minutes. (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (600 mg, 1.946 mmol) was then added followed by N,N-diisopropylethylamine (0.680 mL, 3.89 mmol) and the reaction stirred for 18 h. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (40 mL). The organic layer was washed with further water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, 40 M cartridge, eluting 0-75% EtOAC in isohexane and the solvent evaporated to give the title compound (587 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].I[CH2:22][CH2:23][CH2:24][Si:25]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C(#N)C>[CH2:30]([O:29][Si:25]([O:32][CH2:33][CH3:34])([O:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][N:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:31]
Reactant: CCO[Si](CCCI)(OCC)OCC
Reactant: C1CNCCNCCCNCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCO[Si](CCCN1CCCNCCNCCCNCC1)(OCC)OCC

Procedure:
72 g (0.359 mol) of cyclam and 15 g of Na2CO3 (dried at 100° C. under 1 mm Hg for 24 h) are placed in 2.5 l of acetonitrile in a 6 l reactor under a stream of nitrogen. The mixture is brought to reflux, a solution of 24.2 g (0.073 mol) of iodopropyltriethoxysilane in 500 ml of acetonitrile is then added dropwise and then the reaction mixture is maintained at reflux for 48 h. After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue and the excess cyclam is filtered off. This operation is repeated three times, the filtrates are combined, the pentane is evaporated and compound 1 is obtained in the form of a colorless oil (15 g, 50.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc(N)ccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)c1ccccc1
Temperature: 80 °C
Yield: 18.9 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-amino(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.32 mmol) in pyridine (3 mL) was added benzoyl chloride (45 μL, 0.38 mmol). The solution was stirred for 12 hours when water (80 mL) was added and the solid filtered. The solid was then taken up in methanol (3 mL) and 6N HCl (3 mL) and heated to 80° C. for 3 hours. Water (80 mL) was then added and the solid filtered and dried to give the title compound (20 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.3 (br s, 1H), 10.37 (s, 1H), 8.57 (s, 1H), 8.0–7.9 (m, 5H), 7.78 (d, 1H), 7.6–7.5 (m, 4H), 7.40 (t, 2H); ES-MS (m/z) 332 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>C(O)C>[CH:31]1([NH:34][C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(NC3CC3)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 385 mg (6.74 mmol) of cyclopropylamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 385 mg (6.74 mmol) of cyclopropylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. This was followed by stirring in the microwave at 90° C. for 1 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 95.3 mg (61% of theory)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1I
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
29.30 g (100 mmol) of 2-iodo-5-nitrobenzoic acid are suspended in a mixture of 200 ml of DCM and 1 ml of DMF as solvent. 19.04 g (150 mmol, 1.5 equivalents) of oxalyl chloride are slowly added dropwise at room temperature. The mixture is then stirred at room temperature for two hours and at 30° C. for 30 min. This is followed by evaporation in a rotary evaporator, and the resulting crude product is employed in the following stage.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:16][NH2:17])=O)=O)(C)(C)C.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](N)=[NH:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(O)(=O)C>CN(C=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:16][N:17]=[C:29]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=3[CH:25]=2)[N:30]=1
Reactant: N=C(N)c1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(-c3n[nH]c(C4CCCCN4)n3)cc2N1
Temperature: 120 °C

Procedure:
1.5 mmol of 2-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml DMF. 1 eq of 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine and 90 ul acetic acid were added and the reaction mixture heated to 120° C. overnight. The solvent was evaporated and the crude extracted from ethylacetate/water. The resulting oil was taken up in 15 ml DCM and treated with 3 ml TFA. The reaction mixture was reduced to dryness.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[C:6]([C:29]4[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=4)[CH:7]=[CH:2][CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Product: CNC(=O)c1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (101 mg, 0.286 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (150 mg, 0.57 mmol) and K2CO3 (236 mg, 1.71 mmol) in DME-water (2:1) was added Pd(PPh3)4 (33 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide. 1H NMR (TFA salt, CD3OD) d (ppm): 8.97 (s, 1H), 8.23 (d, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.78 (m, 2H), 7.5 (d, 1H), 7.37 (s, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.08-3.21 (m, 5H), 3.0 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14].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>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14]
Reactant: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
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@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (30 mg, 0.181 mmol), (cis)-1-acetyl-6-bromo-2-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 90) (40 mg, 0.107 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was treated with potassium carbonate (45 mg, 0.326 mmol) and the resulting mixture was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave 4-[(cis)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (20 mg, 0.048 mmol, 45%)
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][S:26][CH3:27].C(OC(=O)C)C.C1CCCCC1>C(OC(=O)C)C.C1CCCCC1>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][S:26][CH3:27])[C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:20]
Reactant: CNCCCSC
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CSCCCN(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C

Procedure:
This was prepared by coupling BOCMePheOH with N-methyl-3-methylthiopropylamine by the method of Example 1(b). The pure product was obtained after silica gel column chromatography in ethylacetate/cyclohexane (1:3). Rf=0.52 (ethylacetate:cyclohexane, 1:1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[NH2:11][C:12]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]2)=[CH:25][C:13]=1[C:14]([NH:16][CH2:17][C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15].C(N(CC)CC)C.C[Si](Cl)(C)C>C(Cl)Cl>[C:20]([NH:19][C:18](=[O:24])[CH2:17][N:16]1[C:14](=[O:15])[C:13]2[C:12](=[CH:28][CH:27]=[C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)[CH:25]=2)[N:11]=[C:5]1[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)N1CCCN(c2ccc(N)c(C(=O)NCC(=O)NC(C)(C)C)c2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(F)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
3-Fluorobenzoyl chloride (24 mg, 0.154 mmol, 0.019 mL) was added to an ice-water cooled solution of 2-amino-N-(tert-butylcarbamoylmethyl)-5-(4-isopropylperhydro-1,4-diazepin-1-yl)benzamide (INTERMEDIATE V.49) (60 mg, 0.154 mmol) and triethylamine (716 mg, 0.96 mL, 7.09 mmol) in DCM (2 mL). Stirring was continued for 15 min. Trimethylsilyl chloride (251 mg, 0.295 mL, 2.31 mmol) was added and the reaction mixture heated in the microwave at 150° C. for 7 min. The reaction mixture was diluted with DCM (10 mL) and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH:NH3 (95:4:1, v/v) as eluent. Further purification by preparative HPLC afforded N-tert-butyl-2-[2-(3-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 7d) (5 mg, 10 μmol, 7%).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
A solution of hydrochloric acid (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (40 mg, 0.084 mmol) in 5:1 dichloromethane-methanol (2.5 mL) at 0° C. After 4 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-diethyl ether, filtered, washed with pentane and dried under reduced pressure to provide a light yellow solid (33 mg, 76%). MS (LCMS) m/z 391.4 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3 H) 2.30-2.42 (m, 1 H) 2.56-2.69 (m, 1 H) 3.08 (s, 3 H) 3.93-4.06 (m, 1 H) 4.32 (td, J=11.76, 4.98 Hz, 1 H) 6.75 (s, 1 H) 7.00 (d, J=6.24 Hz, 1 H) 7.11 (d, J=16.39 Hz, 1 H) 7.30-7.42 (m, 3 H) 7.47 (d, J=16.39 Hz, 1 H) 7.62 (d, J=7.02 Hz, 2 H) 7.75 (s, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Cl>>[N+:23]([C:22]1[C:17]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Product: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 56.0 g (0.28 mole) of 2-aminobenzophenone and 49.6 g (0.31 mole) of 2-chloro-3-nitropyridine was heated by means of an oil bath with stirring at 150° C. for 45 minutes (evolution of hydrogen chloride gas ceased). The product was partitioned between 130 ml of methylene chloride and 250 ml aqueous bicarbonate solution. The aqueous layer was extracted three times with 50 ml portions of methylene chloride. All methylene chloride solutions were combined and dried over sodium sulfate and filtered. Methylene chloride was stripped off in a rotary vacuum evaporator to give a dark brown viscous oil. The product was purified by column chromatography, eluting with methylene chloride on silica gel. On evaporation of the methylene chloride, an orange oil was obtained which crystallized slowly. The crystals were triturated in 105 ml of 1:1 tert-butyl alcohol/petroleum ether (30→60). Crystalline yellow solid, 50.5 g (58%) was obtained by contrifuging and drying, m.p. 85° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Cl[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Reactant: CC(C)n1ncnc1C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Yield: 53.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (50.9 mmol) and potassium bicarbonate (20.4 g, 202.5 mmol) in THF (128 mL) and water (21 mL) was heated to reflux and treated with a solution of 2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.55 g, 50.9 mmol) in THF (25 mL) added dropwise. The reaction mixture was heated at reflux for 24 h before removal of volatile solvent in vacuo. The resultant residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), treated with charcoal (15 g), filtered and concentrated in vacuo to give a solid. The solid was triturated with 10% diethyl ether in pentane then dried at 50° C. in vacuo to give 4-Chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine as a pale brown solid (8.74 g, 54%). LCMS RT=2.86 min, [M+H]+=319/321. 1H NMR 400 MHz (CDCl3) δ: 9.03 (1H, s), 7.89 (1H, s), 7.83 (1H, s), 7.26 (1H, s) 6.88 (1H, s), 4.01 (3H, s), 1.58 (6H, d, J=6.63 Hz).