Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=O.[H-].[Na+].CS(C1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1)(=O)=O.[OH-].[Na+]>CN(C)C=O>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:1]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[N+:11]([O-:13])=[O:12])[N:25]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Nc2ccc(C)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N-formyl-4-methyl-2-nitroaniline (25.00 g) was dissolved in dimethylformamide (400 ml), and sodium hydride (60% purity, oily) (6.11 g) was added thereto at room temperature. After stirring for 10 minutes, 2-methylsulfonyl-4,6-dimethoxypyrimidine (30.28 g) was added at room temperature, followed by stirring for 3 hours. A 10% NaOH aqueous solution was added thereto, and the crystals were collected by filtration, washed with water and dried to obtain 37.50 g of the desired product as a yellow powder (m.p. 158-161° C.).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][OH:15])[NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:9]2
Reactant: OCc1cc2c(OCC3CO3)cccc2[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc2c(OCC3CO3)cccc2[nH]1

Procedure:
11.5 g. 4-(2,3-epoxypropoxy)-2-hydroxymethyl-indole (see U.S. Pat. No. 3,705,907) were dissolved in 100 ml. pyridine. To this solution were added dropwise, while cooling to 0° - 5° C., 6.5 g. (6.7 ml.) pivaloyl chloride. After an hour, the reaction mixture was poured on to ice and extracted with diethyl ether. The ethereal solution was successively washed with dilute sulfuric acid, aqueous sodium bicarbonate solution and water. After drying and treating with active charcoal, the solution was filtered and evaporated. The residue (13 g.; 82% of theory) crystallized upon triturating with diethyl ether/ligroin to give 4-(2,3-epoxypropoxy)-2-pivaloyloxymethyl-indole; m.p. 129° - 131° C.
Reaction SMILES: C(=O)([O-])O.[Na+].[Br-].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH2:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([C:15]2[CH:7]=[C:8]3[N:9]([CH:14]=2)[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc[n+]1CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2cc3ccccn3c2)cc1
Yield: 69 %

Procedure:
A solution of sodium hydrogen carbonate (10.5 g, 120 mmol) in water (125 mL) was added to 2-methyl-1-(2-oxo-2-phenyl-ethyl)-pyridinium bromide (35.0 g, 120 mmol) and the reaction heated to reflux for 30 min. The resultant solid was filtered, washed with water and then dried under vacuum to yield 2-phenyl-indolizine (16.0 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=O)[CH:5]2[CH3:13].B.CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH2:6][CH:5]2[CH3:13]
Reactant: CC1C(=O)Nc2cc(F)c(F)cc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1CNc2cc(F)c(F)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 1.6 g (8.7 mmol) 5,6-difluoro-3-methyl-1,3-dihydro-indol-2-one were placed in 50 mL THF. 18 mL (18 mmol) 1 M borane in THF were slowly added dropwise. The reaction mixture was stirred for 2 h at 70° C. After cooling to RT 10 mL methanol and 30 mL semiconc. HCl were successively added dropwise and then the mixture was refluxed for 1 h. After cooling to RT it was extracted with EtOAc. The aqueous phase was made alkaline with 4M NaOH solution and extracted with DCM. The organic phase was dried, filtered and evaporated down.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)n2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 262.9 %

Procedure:
To the above prepared N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide (0.110 g, 0.19 mmol) was added TFA (6 mL) and the reaction mixture was stirred at 50° C. for 2 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.235 g, 100%). MS (ISP) 471.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([N:16]1[C:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=O)=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:9]([N:16]1[C:20]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCc1cncn1Cc1ccccc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCc1cncn1Cc1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Magnesium turnings (0,49 g) are covered with 4 ml of dry tetrahydrofuran. Brombenzene (3,18 g) in 7 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. The reaction mixture is refluxed for an additional hour. Ethyl 4-(1-benzyl-1H-imidazol-5-yl)butyrate (1,10 g) in 15 ml of dry tetrahydrofuran is then added dropwise to the Grignard reagent and the reaction mixture is refluxed for 2 hours. Saturated ammonium chloride is added to the cooled reaction mixture. Tetrahydrofuran is evaporated and the precipitated product is collected. Yield 1,41 g. Melting point of the hydrochloride salt is 197°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[O:16][CH2:17][CH2:18][C:19]=12)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: O=C(O)c1cccc2c1CCO2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2c1CCO2

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 2,3-Dihydro-benzofuran-4-carboxylic acid.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][NH:54][CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]>CN(C=O)C>[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:48]([C:50]1[S:51][C:52]2[CH2:53][N:54]([C:9](=[O:11])[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:55][CH2:56][C:57]=2[N:58]=1)=[O:49]
Reactant: O=C(O)COc1ccccc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)COc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of phenoxy acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatograph to obtained the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)=CC=1)([O-])=O>CO>[CH:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:37]([N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:40][CH:41]=1)([CH3:48])[CH3:47]
Reactant: Clc1ccc2c(C3CCNCC3)ncnc2c1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(Cl)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (29b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (29c) as a di-HCl salt. To a suspension of (29c) in anhydrous MeOH, was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol) and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5 mg (12% overall yield from 29a) of pure 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.25 (s, 1H), 8.15-8.06 (m, 2H), 7.62 (d, 1H), 7.23 (d, 2H), 6.85 (d, 2H), 6.30 (s, 1H), 4.49 (m, 1H), 4.26 (m, 2H), 3.70 (m, 1H), 3.15 (m, 2H), 2.23-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 424.2, found 425.4 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32]>ClCCl>[CH2:34]([O:33][C:31](=[O:32])/[CH:30]=[CH:29]/[C:28]1[CH:36]=[CH:37][CH:38]=[C:26]([NH:25][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=1)[CH3:35]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: CCOC(=O)/C=C/c1cccc(N)c1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 500 mg (1.85 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 369 mg (1.93 mmol) of ethyl 3-amino-trans-cinnamate to 150° C. for 1.5 h. After cooling, add dichloromethane and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 20:1). 539.5 mg (73.9% of theory) of the target product are obtained as a yellowish solid.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][O:49][CH2:48]5)=[CH:41][C:40]=4[F:53])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[F:53][C:40]1[CH:41]=[C:42]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][O:49][CH2:48]2)[CH:43]=[C:44]([F:45])[C:39]=1[C:34]1[N:33]=[C:32]([C:30]([NH:29][C:12]2[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:31])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(OC4CCCOC4)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCC3O)C1

Procedure:
The amide intermediate was treated with THF (0.7 mL), MeOH (0.7 mL) and 1.0 M aq. NaOH (0.74 mL, 0.74 mmol) at room temperature for 20 min. The volatile organic solvents were removed. The residue was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give an alcohol intermediate, tert-butyl ((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](Br)=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])CCC.[B:35](OC)([O:38]C)[O:36]C.Cl>C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([B:35]([OH:38])[OH:36])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COB(OC)OC
Reactant: Brc1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-bromonaphthalene and 50 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 3.2 ml (8 mmol) of n-butyllithium (2.5M in hexane) were added dropwise at -78° C. and stirring was carried out for 15 minutes, at the same temperature. 2.1 g (20 mmol) of trimethyl borate were added and stirring was carried out for 2 hours. 23 ml of hydrochloric acid (1N) were added at -50° C. and the temperature was permitted to increase to room temperature. The reaction mixture was extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane, filtered and dried. 2.8 g (100%) of the expected boronic acid were collected, which acid was used, as is, in the synthesis to follow.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[C:13]([Br:15])[C:12]([Cl:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].O.[Sn](Cl)Cl>O.Cl>[ClH:16].[Br:15][C:13]1[C:12]([Cl:16])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:5][NH2:1])[CH:14]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)c(Cl)cc1C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 213.5 %

Procedure:
A solution of sodium nitrite (3.03 g, 43.9 mmol) in water (14.8 mL) was added dropwise to a cooled (−10° C., NaCl-ice bath) suspension of 2-amino-4-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in 37% aqueous HCl (39.9 mL) and water (13.3 mL), at such rate that the temperature did not exceed 0° C. The resulting suspension was stirred at 0° C. for 15 min, then was treated with a solution of tin(II) chloride hydrate (22.7 g, 120 mmol) in 37% aqueous HCl (17 mL). The resulting mixture was warmed to room temperature and stirred for 60 min. The precipitate was collected by filtration, washed with water and air-dried overnight to give 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride as an off-white solid (12.86 g, 96% yield). Mass spectrum m/z 365, 267 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (br. s., 1H), 7.95 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:39]1[S:40][C:41]2[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(CC)CC)C3)sc12
Yield: 18.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidine-1-carboxylate obtained in Example (215a) (49.0 mg, 0.111 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (35 mg, 0.122 mmol) and sodium carbonate (118 mg, 1.11 mmol), to obtain 11 mg of the title compound (18%) as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][N:33]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: Cc1ccc(C(=O)Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C)nc3)cc2)c2ccccc12
Yield: 72.5 %

Procedure:
Ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (258 mg, 0.83 mmol) and triethylamine (0.4 mL, 2.87 mmol) were dissolved in dichloromethane (15 mL), and in an ice bath, dichloromethane solution (10 mL) of the prepared 6-methylnicotinoyl chloride (about 1.00 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, and chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 258 mg, at a yield of 72.3%.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[N:18][O:19][CH2:20][C:21]([NH:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32])[C:26]([O:28]C)=[O:27])=[O:22])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[Li+].[OH-]>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:8]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]=[N:18][O:19][CH2:20][C:21]([NH:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32])[C:26]([OH:28])=[O:27])=[O:22])=[CH:15][CH:16]=1)(=[NH:9])[NH2:10]
Reactant: CCCCOC(=O)N[C@@H](CNC(=O)CON=Cc1ccc(C(=N)N)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N[C@@H](CNC(=O)CON=Cc1ccc(C(=N)N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
Methyl 3-[2-[[(4-amidinophenylmethylene)amino]oxy]-1-oxoethylamino]-2-(S)-[n-butyloxycarbonylamino]-propanoate TFA salt (91 mg, 0.17 mmol) was dissolved in 1.5 mL of methanol and 0.51 mL of 1M LiOH was added. After stirring at room temperature for 16 hours, the reaction mixture was evaporated in vacuo and the residue was dissolved in 2 mL of 1:1 CH2Cl2/TFA. This solution was evaporated in vacuo and the residue was purified by preparative HPLC (Dynamax-300A C18 reverse phase column; 21.4×250 mm; 10 ml/min flow rate; 254 nM; gradient: from 100% H2O with 0.05% TFA to 20% H2O and 80% CH3CN with 0.05% TFA in 50 minutes) to yield 63 mg of desired product as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.39 (bs, 2H), 9.2 (bs, 2H), 8.44 (s, 1H), 7.99 (t, 1H), 7.83 (m, 4H), 7.36 (d, 1H), 4.6 (s, 2H), 4.05 (m, 1H), 3.9 (m, 2H), 3.55 (m, 1H), 3.36 (m, 1H), 1.46 (m, 2H), 1.3 (m, 2H), 0.85 (t, 3H); MS (ESI): m/e 408.2 (M+H)+; HRMS (FAB), e/z Calc. for (M+H)+: 408.188309, Found: 408.189211.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])=[O:15])[S:13][C:6]=12.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])(=[O:32])=[O:15])[S:13][C:6]=12
Reactant: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 233 (50 mg, 0.142 mmol) in DCM (2 mL), was added mCPBA (77%, 33 mg, 0.142 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, water was added and the phases were separated. The organic layer was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 236 (46 mg, 88% yield, crude) as a yellow solid which was used in the next step without additional purification. MS (m/z): 369.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN
Solvent: CCO
Product: CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of 2.0 g of 4-chloro-3-nitroquinoline in 20 ml of dry ethanol is added 15 ml of 30% methylamine in ethanol. The mixture is stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is triturated with excess water. The resulting crystals are collected by filtration and washed repeatedly with water. The crystals are dried over phosphorus pentoxide in vacuo to afford 1.82 g (93%) of 4-methylamino-3-nitroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 72 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (55 mg, 72%) which was obtained as a white solid. MS: m/e=384.0 [M+H]+.