Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.P(=O)(O)(O)O.O=[CH:29][C:30](=[CH2:32])[CH3:31].O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:31][C:30]([CH3:32])=[CH:29]2
Reactant: Nc1cc(F)ccc1Br
Reactant: C=C(C)C=O
Agent: N
Agent: O=P(O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: O
Product: Cc1cnc2c(Br)ccc(F)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
2-Bromo-5-fluoro-aniline (2.50 g, 95 mass % article, 12.5 mmol), m-nitrobenzenesulfonic acid (1.33 g, 6.53 mmol), 10.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (34.8 mg, 0.125 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2.32 g of methacrolein (98 mass % article, 32.5 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 730 mg of 8-bromo-5-fluoro-3-methyl-quinoline as a yellow white solid (yield: 24.3%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([OH:41])=O)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([NH2:57])[CH:55]=3)[N:50]([C:58]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([NH:57][C:54]2[CH:55]=[C:56]3[C:51](=[CH:52][CH:53]=2)[N:50]([C:58]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:49]=[C:48]3[C:45]2[CH:44]=[CH:43][N:42]=[CH:47][CH:46]=2)=[O:41])[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CC(Cc2ccccc2)CC(C(=O)O)C1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(Cc2ccccc2)CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 5-benzyl-1-methylpiperidine-3-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:36]#[N:37])[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(Br)n2)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(C#N)n2)C1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), zinc cyanide (250 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) were suspended in 8 ml of dimethylformamide (DMF), followed by stirring under a nitrogen atmosphere at 110° C. for 9 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1→3:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 398 mg of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[N:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=2>>[OH:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=[CH:3][C:2]=1[NH-:1].[OH:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH-:13]
Reactant: Nc1cnc2ccccc2c1O
Reactant: Nc1cnc2cccnc2c1O
Product: [NH-]c1cnc2ccccc2c1O
Product: [NH-]c1cnc2cccnc2c1O

Procedure:
In step (1) of Reaction Scheme VI, a 3-amino[1,5]naphthyridin-4-ol or 3-aminoquinolin-4-ol of Formula XXX is reacted with an acyl halide of Formula R2C(O)Cl or R2C(O)Br to provide an N-(4-hydroxy[1,5]naphthyridin-3-yl)amide or N-(4-hydroxyquinolin-3-yl)amide of Formula LVIII. The reaction can be carried out using the method described in step (2) of Reaction Scheme I.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:31]([O-:33])=[O:32]>ClCCl>[N+:31]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])=[CH:23][CH:22]=[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:20]=2)([O-:33])=[O:32]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A solution of 1,2-diamino-2-methylpropane (9.3 mL, 88.9 mmol) and triethylamine (5.0 mL, 35.5 mmol) in dichloromethane (100 mL) was cooled to 0° C. A solution of 4-chloro-3-nitro-7-phenylquinoline (5.06 g, 17.8 mmol) in dichloromethane (50 mL) was added over a period of 45 minutes, and then the reaction was allowed to warm to ambient temperature. The solution was washed sequentially with water (2×100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:13][C:14](C)(C)C([O-])([O-])[O-]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[N:6]([C:13]([CH3:14])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1nnc2c([N+](=O)[O-])cc(Br)cn12
Temperature: 80 °C

Procedure:
A suspension of 5-bromo-3-nitro-2-hydrazinopyridine (2.0 g, 8.58 mmol) in trimethylorthoacetate (20 mL) was heated at 80° C. for 20 h. After cooling, the solvent was distilled off, the residue was dissolved in ethyl acetate (200 mL), washed with water, brine, dried over sodium sulphate and concentrated to provide the product 6-bromo-3-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[CH3:9][C@H:10]1[CH:14]=[CH:13][C@@H:12]([CH3:15])[N:11]1[CH2:16][C:17](OC)=[O:18].Cl>C(O)(C)C.CO>[NH2:4][C:3]([NH2:5])=[N:2][C:17](=[O:18])[CH2:16][N:11]1[C@H:12]([CH3:15])[CH:13]=[CH:14][C@@H:10]1[CH3:9]
Reactant: COC(=O)CN1[C@H](C)C=C[C@@H]1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: C[C@@H]1C=C[C@H](C)N1CC(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of guanidine hydrochloride (0.6 g.) sodium methoxide (from 0.138 g. of sodium), and methanol (5 cm3) was stirred at room temperature for 1 hour. Methyl cis-(2,5-dimethyl-2,5-dihydropyrrol-1-yl)acetate was then added (0.6 g.) and the mixture stirred overnight (16 h.). The solution was then evaporated and the residue partitioned between water (1.5 cm3) and ether (3 cm3). After stirring at 0° C. for about 3 hours a white precipitate separated. The precipitate was collected and washed with water and ether to give 0.24 g. of title base. The base was dissolved in isopropyl alcohol (3 cm3) and acidified with ethanolic hydrogen chloride. On cooling in ice the title compound hydrochloride was collected and washed with isopropyl alcohol. The product was then dissolved in hot ethanol (3 cm3) diluted with ethyl acetate (2 cm3) and cooled to give pure title compound as the hydrochloride (0.15 g.), m.p. 207°-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[C:16](=[O:27])[NH:17][N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:20]=1)=O>C(O)(=O)C>[O:27]=[C:16]1[C:15]([C:13]2[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[N:12]=2)=[CH:20][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:18][NH:17]1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2cc(-c3ccncc3)n[nH]c2=O)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
A mixture of 1.3 g of methyl 4-amino-3-[(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carbonyl)amino]benzoate and 20 ml of glacial acetic acid is heated with stirring at 100° C. for 10 hours. The precipitate which has formed is filtered off with suction, washed with water and dried in vacuo at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:9]1[CH2:14][CH2:13][CH:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Oc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-aminophenol (1 g, 9.164 mmol), tetrahydropyran-4-one (1.099 ml, 11.913 mmol), and sodium triacetoxyborohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred at room temperature for 16 h. The crude mixture was filtered over diatomaceous earth, washed with DCM and the filtrate was evaporated in vacuo to yield D2O (0.69 g) which was used as such in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][C:17]1[NH:21][C:20](=[O:22])[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C1CCCCC1.C(OCC)(=O)C>CC(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][N:21]2[C:20](=[O:22])[C:19]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:18]=[C:17]2[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)c1ccc(C(=O)CN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1
Temperature: 70 °C
Yield: 48.1 %

Procedure:
To a mixture of 4-(2-bromo-acetyl)-benzoic acid ethyl ester (812 mg, 3 mmol) and 2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (750 mg, 3 mmol) in 12 mL acetone, potassium carbonate (502 mg, 3.6 mmol) is added and the reaction mixture is heated at 70° C. for 5 min in the microwave oven (Biotage Initiator). The mixture is cooled to room temperature, filtered and the filtrate evaporated to yield the crude product which is subjected to flash chromatography. ISCO Companion CombiFlash, 80 g silica gel, cyclohexane/ethyl acetate, gradient, ethyl acetate 0-100% to yield 4-[2-(2-methyl-5-oxo-4,4-diphenyl4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid ethyl ester (635 mg, 45%) as light yellow solid. LC/MS at 254 nm; [M+H] 441; Rt 3.613 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[N:71]1([CH:77]2[CH2:82][CH2:81][N:80]([C:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:9]5[N:10]=[C:11]([N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[N:12]=[C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)[N:8]=5)=[CH:24][CH:23]=4)=[O:37])=[CH:36][CH:35]=3)=[O:33])[CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 60.1 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][C:17]([NH:19][CH2:20][C:21]#[N:22])=[O:18])[O:8][C@H:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][C:17]([NH:19][CH2:20][C:21]3[NH:33][N:32]=[N:31][N:22]=3)=[O:18])[O:8][C@H:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N1C(=O)[C@@H](CC(=O)NCC#N)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Na+]
Product: CC(C)N1C(=O)[C@@H](CC(=O)NCc2nnn[nH]2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and sodium azide were subjected to the same procedure as in Example 102 to yield a crystal.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=1)[C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:5])C>O1CCOCC1>[C:4]([CH2:6][CH:7]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC(c1ccc(C(=O)OCC)cc1)c1c[nH]c2cc(OCCCNc3ccccn3)ccc12
Solvent: C1COCCO1
Product: O=C(O)CC(c1ccc(C(=O)O)cc1)c1c[nH]c2cc(OCCCNc3ccccn3)ccc12

Procedure:
Analogously to Example 1.7, ethyl 4-(2-ethoxycarbonyl-1-{6-[3-(pyridin-2-ylamino)propoxy]-1H-indol-3-yl}ethyl)benzoate, prepared analogously to Example 1.1-1.6, is stirred with dioxane/1N NaOH, giving 4-(2-carboxy-1-{6-[3-(pyridin-2-ylamino)propoxy]-1H-indol-3-yl}ethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>O1CCOCC1>[C:18]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(C)NC1=NS(=O)(=O)c2cc(N)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(NC(C)C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-amino-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.18 g) and acetic anhydride (0.6 mL) in dioxane (2 mL) was stirred for 1 h at room temperature. The medium was then mixed with water (5 mL) and stirred for 1 h. The solvents were removed by distillation under reduced pressure and the residue of the crude title compound was recrystallized from methanol-water to give the title compound (yield: 0.16 g); m.p. 260-262° C.; IR (KBr): 3353, 3316, 3240, 3101, 3069, 2974, 1672, 1624, 1608, 1581, 1546, 1497, 1467, 1391, 1279, 1159, 1142, 1123, 1104 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 2.00 (s, 3H, COCH3), 3.90 (m, 1H, NH—CH), 6.85 (bd, 1H, NH—CH), 7.05 (d, 1H, 5-H), 7.60 (bd, 1H, 6-H), 8.00 (bs, 1H, 8-H), 10.00 (bs, 1H, CONH), 10.10 (bs, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH2:15][C:16](OC)=[O:17])=[N:7][CH:6]=1)[CH3:2]>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][C:8]2[O:14][CH2:15][C:16](=[O:17])[NH:11][C:9]=2[CH:10]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)c1cnc(OCC(=O)OC)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(c1)NC(=O)CO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 6-methoxycarbonylmethoxy-5-nitro-nicotinic acid ethyl ester (3.271 g) in acetic acid (25 ml) was added iron powder (9.64 g). The mixture was stirred for 2 h at 60° C. The mixture was filtered and the filter cake was washed with acetic acid, EtOAc, EtOH, dichloromethane and with MeOH. The filtrate was concentrated. The residue was suspended in CH2Cl2/MeOH 9:1 and passed with more of the same solvent mixture over silica gel to give the title compound (1.52 g) as a light brown solid. MS (m/e)=223.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][NH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19]N(C)C=O.[H-].[Na+].FCOS([O-])(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH3:19])[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(Cl)c1
Reactant: CN(C)C=O
Agent: O=S(=O)([O-])OCF
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1Cc2cccnc2N(c2cccc(Cl)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a solution of 2.6 g of 1-(m-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dimethylformamide was added 0.6 g of sodium hydride and the mixture was stirred for 15 minutes. To this was further added 3.4 g of fluoromethylsulfate, and stirring was continued for 1.5 hours at room temperature. After the reaction was finished, the solvent was distilled off from the resulting mixture under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate, and the residue was recrystallized from a mixture of ether and petroleum ether to give 2.1 g of 1-(m-chlorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 139° - 140° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:24]1[CH2:23][CH2:22][CH:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1)=[O:4])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g (37.3 mmol) tert-butyl[4,4′]bipiperidinyl-1-carboxylate in 100 mL EtOH and the reaction mixture was refluxed for 2 h. To complete the reaction a further 1 mL (9.2 mmol) of ethyl acrylate were added, the mixture was refluxed for 1 h and left overnight at RT. The solvent was eliminated i. vac. and the crude product was further reacted without being purified.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Cl:14])=[CH:9][CH:8]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH3:15])[C:5]([CH2:3][NH:2][CH3:1])=[CH:13]2
Reactant: CNC(=O)c1cc2cc(Cl)ccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2cc(Cl)ccc2n1C
Temperature: 0 °C

Procedure:
To an ice-cold solution of 5-chloro-1-methyl-1H-indole-2-carboxylic acid methylamide (2.12 g, 9.5 mmol) in THF (15 mL) was added lithium aluminum hydride (19 mL of a 1 M solution in THF, 19.0 mmol). Once the addition was complete, the resulting slurry was heated to reflux overnight. The mixture was cooled in an ice bath and carefully quenched by the consecutive addition of water (0.90 mL), 15% aqueous NaOH (0.90 mL) and water (2.5 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate concentrated to give the title (2.00 g, quantitative) compound as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=1.8 Hz, 1H), 7.25-1.14 (m, 2H), 6.32 (s, 1H), 3.86 (s, 2H), 3.73 (d, J=4.8 Hz, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[CH3:19])[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude (R)-2-(5-cyano-6-(1-methyl-1H-indol-4-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (151 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 396.4 (M+H); UV 202.2, 273.1, 324.8 nm; t 0.613 min.