Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[Li]CCCC.[CH3:18][S:19]SC>C1COCC1>[CH3:18][S:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1
Reactant: Brc1c[nH]nc1-c1cccnc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c[nH]nc1-c1cccnc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of anhydrous THF (150 ml) containing compound 20A (3.0 g, 13.4 mmol, prepared accordingly to Bioorganic & Medicinal Chemistry, 4, 1996, 227-237) was added 2.1 eq n-BuLi (11.2 ml, 2.5 M in hexane) dropwise at −78° C. under N2. After the addition, the resulting solution was stirred for 2 hours at −78° C. At this temperature 1.1 eq methyldisulfanyl methane (1.33 ml) was added and the resulting solution was stirred for 1 hour at −78° C. and subsequently allowed to warm to ambient temperature overnight. Then the mixture was quenched with a saturated NH4Cl solution at 0° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (ethyl acetate) afforded compound 21A (oil, 1.71 g, 67%). 1H-NMR (200 MHz, CDCl3): δ 9.18 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.28 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.42-7.33 (m, 1H), 2.38 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[N+:26]=[N-:27]
Reactant: COC(=O)[C@H](Cc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A mixture of 1A (1.61 g, 4.0 mmol) and sodium azide (0.78 g, 12.0 mmol) in DMF (27 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with H2O (120 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, step-wise gradient from 2-40% EtOAc in Hexanes) to give 2A (1.46 g, 100%) as a clear oil. 1H NMR (600 MHz, CDCl3): δ 7.05 (2H, d, J=8.4 Hz), 6.85 (2H, d, J=8.4 Hz), 4.97 (1H, d, J=7.8 Hz), 4.51-4.58 (1H, m), 4.13 (2H, t, J=5.4 Hz), 3.71 (3H, s), 3.58 (2H, t, J=5.4 Hz), 3.06 (1H, dd, J=13.8, 5.4 Hz), 3.00 (1H, dd, J=13.8, 5.4 Hz), 1.42 (9H, s); 13C NMR (150 MHz, CDCl3): δ 172.3, 157.3, 155.1, 130.4, 128.7, 114.6, 79.9, 66.9, 54.5, 52.2, 50.2, 37.5, 28.3; MS (ESI, m/z): 387 (M+Na)+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Cl:15])[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH:2]=CC.C[OH:18]>ClCCl>[Cl:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:16])[CH:5]([CH2:1][CH:2]=[O:18])[CH2:14][CH2:13]2
Reactant: CO
Reactant: CC=CCC1CCc2cccc(Cl)c2C1=O
Solvent: ClCCl
Product: O=CCC1CCc2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
7.7 g of 2-(2-buten-1-yl)-8-chloro-1-tetralone were dissolved in a mixture of 220 ml of dichloromethane and 60 ml of methanol, cooled to -75° and the double bond was ozonized in the usual manner. After flushing the reaction mixture with oxygen and argon, 4.8 ml of dimethyl sulfide were added dropwise. The mixture was left to warm slowly to room temperature and was stirred for an additional 15 hours. The crude product (10.8 g) was dissolved in about 100 ml of dichloromethane and added to a mixture of 12 ml of 10% aqueous oxalic acid, 120 g of silica gel and 300 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. 6.4 g (83%) of 8-chloro-2-(2-oxoethyl)-1-tetralone were obtained as a pale brown oil by extraction with dichloromethane.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][C@H:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:15]([F:18])([F:17])[F:16])[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27]
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.850 g, 4.24 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (20 mL), extracted with dichloromethane (3×15 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.70 g (99% yield) of tert-butyl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([NH2:13])=[N:7][NH:8]2.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15].O>CS(C)=O>[NH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[N:8]([CH2:19][C:18]2[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])[N:7]=1
Reactant: Nc1n[nH]c2cccc(Cl)c12
Reactant: N#Cc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(Cn2nc(N)c3c(Cl)cccc32)c1
Reaction time: 2 h

Procedure:
To a suspension of ground potassium hydroxide (421 mg, 7.50 mmol) in anhydrous dimethyl sulfoxide (5 mL) at room temperature under nitrogen was added a solution of 4-chloro-1H-indazol-3-amine (for a preparation see Intermediate 40) (503 mg, 3.0 mmol) in anhydrous dimethyl sulfoxide (15 mL). After 30 minutes 3-cyanobenzyl bromide (Aldrich) (735 mg, 3.75 mmol) was added in one portion. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (200 mL), forming a yellow/brown emulsion. This was extracted using chloroform (2×200 mL). The combined organic solutions were washed with water:brine (1:1) (200 mL), passed through a hydrophobic frit, and evaporated in-vacuo to yield a brown oil. The oil was applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-100% ethyl acetate in cyclohexane gradient over 80 min. Fractions 32-34 were combined and the solvent was evaporated in-vacuo to yield the title compound as an off white solid (216 mg, 25%). LCMS (System B) RT=2.51 min, ES+ve m/z 283 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:9]=3[N:28]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CCO>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:9]=3[N:28]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12

Procedure:
methyl 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 81 mg, 0.219 mmol) was stirred in EtOH (3 ml) and 6N NaOH (1 ml) at 60° C. for 15 hours. Water was added and the mixture acidified using 6 N HCl. The solid was filtered, washed with water and dried. After trituration in MeOH and filtration, 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylic acid was isolated as yellow solid (57 mg, 73% yield)). LCMS (ES): >95% pure, m/z 357 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]2[CH2:25][CH2:24][NH:23][CH2:22][C@@H:21]2[OH:26])=[CH:17][CH:16]=1>>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][C@H:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([CH3:14])=[CH:16][CH:17]=3)[C@H:21]([OH:26])[CH2:22]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: Cc1ccc(C[C@@H]2CCNC[C@@H]2O)cc1
Product: Cc1ccc(C[C@H]2CCN(CCS(=O)(=O)c3ccc(O)cc3)C[C@H]2O)cc1
Yield: 31 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3R,4R)-4-(4-methyl-benzyl)-piperidin-3-ol in 31% yield as a white foam.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCCC1>[CH:17]([CH2:19][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10])=[O:18]
Reactant: C=CC=O
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: N#CC(C#N)(CCC=O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
First, 20 ml of tetrahydrofuran was added dropwise slowly to the mixture of 0.50 g of dihydro tetrakis(triphenylphosphine)ruthenium and 3.00 g of (4-(trifluoromethyl)benzyl)malononitrile under an atmosphere of nitrogen , followed by stirring for 15 minutes. Then, 0.82 g of acrolein was added dropwise slowly, followed by stirring for 1 hour at room temperature and then the solvent was distilled away. The residue was subjected to silica gel column chromatography to give 1.58 g of 2-(2-formylethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (19)).
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42](=O)[C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3/[C:42](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:36]=2[CH:35]=1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)/C(=C\CN1CCCC1)c1ccccc1CO2

Procedure:
Anhydrous 2-(N-pyrrolidinyl)-ethyltriphenylphosphonium bromide (10 g, 45 mmole), 48 mmole of n-butyl lithium in hexane, and 2-bromo-6,11-dihydrodibenz [b,e1-oxepin-11-one (5 g, 35 mmole) were reacted in 300 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This provided the pure Z-isomer (1.76 g) as a light brown solid, mp 108°-109° C.. pmr (DMSO-d6) δ: 7.28-7.50 (m, 6H, aromatic H); 6.80 (d, J=8.8 Hz, 1H, H4); 5.82 (t, 1H, HC=); 5.20 (s, 2H, ArCH2O); 3.29 (m, 2H, NCH2C=); 2.50 (m, 4H, 2NCH2); 1.70 (m, 4H, 2CH2).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1cccc2c1c(N)nn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C

Procedure:
To a solution of 1,1-dimethylethyl 3-amino-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 5) (6.03 g, 22.9 mmol) and 5-chloro-2-thiophenesulfonyl chloride (3.07 mL, 22.9 mmol) in DCM (30 mL) was added dropwise at 0° C. a solution of pyridine (3.7 mL, 46 mmol) in DCM. The reaction mixture was stirred allowing to warm from 0° C. to room temperature over 2 h, then stirred at room temperature over the weekend. Pyridine (50 mL) were added and resulting mixture was stirred at 50° C. for another 24 h. The reaction mixture was then quenched with 50 mL of a saturated NaHCO3 solution. The organic layer was partitioned and the aqueous layer was further extracted with 50 mL of DCM. The organic solutions were combined, washed with water (50 mL) then brine (50 mL), and dried with an hydrophobic frit. The crude product was purified by chromatography on two 100 g Si cartridges on Flashmaster, eluting with 0 to 25% gradient of EtOAc in DCM, over 60 min to give the desired product as a pale orange solid: (2.21 g, 22%). LCMS (System A) RT=1.35 min, ES+ve m/z 444 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC[C@H](CC(C)C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](CC(C)C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide (35 mg, 0.063 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.32 ml, 4.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 16 mg (60%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide as a white solid. MS: [M+H]+=425, 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (s, 1H), 9.13 (s, 1H), 8.53 (dd, J=8.7, 5.3 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.71 (dd, J=9.8, 2.3 Hz, 1H), 7.11 (td, J=9.1, 2.3 Hz, 1H), 4.41 (td, J=9.1, 4.9 Hz, 1H), 4.16 (s, 3H), 3.52 (dd, J=9.4, 4.2 Hz, 1H), 3.46 (dd, J=9.4, 4.2 Hz, 1H), 3.27 (s, 3H), 1.48-1.75 (m, 3H), 0.91 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.0 Hz, 3H).
Reaction SMILES: N[C@H](C(CBr)=[O:8])CC(C)C.[NH:11]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:32](N[C@H](C(CCl)=O)CC(C)C)=[O:33])[CH2:28]C(C)C)=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:11]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:32]([OH:8])=[O:33])[CH3:28])=[O:25])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C[C@H](N)C(=O)CBr
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A mixed anhydride of Z-Phe-Gly-Ala-OH (0.41 g, 0.95 mmol) was prepared and coupled to H-LeuCH2Br.HBR substantially according to the procedure described for preparation of Z-Phe-Gly-Leu-LeuCH2Cl, above. The resulting product was crystallized from ethyl acetate:hexane to yield 0.30 g. Product was recrystallized from the same solvents to yield 0.07 g, m.p. 135.5°-138° (dec.).
Reaction SMILES: [CH2:1]([N:3](C=O)[N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]1)[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([NH:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1)[CH3:2]
Reactant: CCOC(=O)c1cn(N(C=O)CC)c2cc3c(cc2c1=O)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Reaction time: 1 h
Yield: 120.7 %

Procedure:
To a stirred suspension of 2 g (0.006 mole) of ethyl 5-[ethyl(formyl)amino]-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 8) in 53.8 ml of refluxing ethanol was added a solution of 0.9 g (0.014 mole) of potassium hydroxide in 3 ml of water over a period of about two minutes. After a few more minutes of reflux, 30 ml of additional ethanol was added and reflux continued for one hour. The reaction mixture was allowed to stand overnight, then chilled in an ice-bath, and the solid product was collected by filtration and washed with absolute alcohol and ether to give 2 g of 5-(ethylamino)-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid in the form of its potassium salt hemihydrate, m.p. 242° C. (decompn.) after being dried for several days at 75° C. (0.1 mm).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[N:22]1([C:19](=[O:21])[CH2:20][C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
10.2 g of diisopropylamine (0.1 mol) was placed in 100 ml dry THF under nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium in hexane (2.5 M, 0.1 mol) was slowly added dropwise. When the addition was completed the mixture was allowed to stir for 60 minutes and then acetylmorpholine 12.9 g (0.1 mol) was added dropwise. The reaction mixture was stirred for 20 min in the freezing mixture. In a second flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF was cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 150 ml ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.). 5.0 g of product were obtained in the form of white crystals with a melting point of 60° C. after crystallization from PE (petrol ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:41])[CH2:11][C:12](=[O:40])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C@H:23]([NH:31]C(OC(C)(C)C)=O)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:31][C@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:40])[CH2:11][C:10](=[O:41])/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:17]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N[C@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-(4-hydroxyphenyl)-7-[4-((R)-2-tert-butoxycarbonylamino-3-phenylpropionylamino)phenyl]hepta-1,6-diene-3,5-dione (30 mg, 54 μmol, synthesized in Example 279) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=97/3 to 85/15). The product was obtained as a solid (9.2 mg, 37%) having the following characteristics.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:6])[CH3:5])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]([NH2:1])([CH3:5])[CH3:6])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)c1ccc2ncccc2c1
Reaction time: 6 h
Yield: 15.9 %

Procedure:
To 6-(2-azidopropan-2-yl)quinoline (0.100 g. 2.67 mmol) in ethanol (3 ml), palladium on carbon (10 mg, 10% w/w) was added and stirred under a hydrogen atmosphere using hydrogen filled balloon. After 6 h, the reaction mass was filtered through celite, washed with methanol and concentrated to afford the title compound as brown liquid (0.079 g, 90%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.82 (dd J=4.2, 1.6 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.9, 2.1 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (q, J=4.2 Hz, 1H), 2.06 (s, 2H),1.46 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:16]O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:3]([C:4]([O:6][CH3:16])=[O:5])=[CH:7][CH:8]=[CH:9][NH:10]1
Reactant: O=C(O)c1cccnc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc[nH]c1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
To a flask is added 2-hydroxynicotinic acid (10 g, 72 mmol), concentrated H2SO4 (2 mL) and MeOH (400 mL), followed by toluene (80 mL). The reaction mixture is heated to reflux overnight with a Dean-Stark trap. After cooling to RT, the mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM (200 mL), neutralized with saturated aqueous NaHCO3 to pH 7 and extracted with DCM (200 mL) for three times. The combined organic phases are dried and concentrated to give the desired product (8.2 g, 74% yield). MS (m/z): 153.9 (M+H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27]([Cl:34])[CH:26]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2[N:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)=[O:33])=[C:27]([Cl:34])[CH:26]=1
Reactant: CCCCNc1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, butyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine (example 4.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 5 d under reflux conditions to give the title compound as colorless foam. MS: m/e=510.9 [M+H+].